IE903216A1 - New thiazole derivatives, processes for the preparation¹thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

A compound of the formula : wherein R<1> is amino which may have suitable substituent ( s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : in which R<4> is hydrogen, cyano or acyl, and R<5> is amino or lower alkoxy, R<2> and R<3> are each hydrogen, acyl or lower alkyl which may have halogen; or R<2> and R<3> are linked together to form lower alkylene, in which R<6> is hydrogen or halogen, and A is bond or lower alkylene, provided that when R<1> is amino which may have suitable substituent(s) and A is bond; or R<1> is lower alkylthioureido and A is lower alkylene, then and pharmaceutically acceptable salt thereof, processes for their preparation and pharmaceutical compositions comprising them as an active ingredient.

Description

NEW THIAZOLE DERIVATIVES, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME This invention relates to new thiazole derivatives and pharmaceutically acceptable salts thereof.

More particularly, it relates to thiazole derivatives and pharmaceutically acceptable salts thereof which have 5 antiulcer activity and ^-receptor antagonism, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment of ulcer in human being or animals.

Accordingly, one object of this invention is to 10 provide new thiazole derivatives and pharmaceutically acceptable salts thereof which possess antiulcer activity and H^-receptor antagonism.

Another object of this invention is to provide processes for the preparation of said thiazole derivatives and salt thereof.

A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said thiazole derivatives or pharmaceutically acceptable salts thereof.

Still further object of this invention is to provide a therapeutical method for the treatment of ulcer in human being or animals.

The thiazole derivatives of this invention are new and can be represented by the following general formula (I) : R2NH N--Y-A-R1 VU! J wherein R^ is amino which may have suitable substituent (s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : N-R -C-R' in which R4 is hydrogen, cyano or acyl, and R5 is amino or lower alkoxy, a and R are each hydrogen, acyl or lower alkyl which may have halogen; or and R are linked together to form lower alkylene, Y in which R is hydrogen or halogen, and A is bond or lower alkylene, provided that and when RX is amino which may have suitable substituent (s) and A is bond; or RX is lower alkylthioureido A is lower alkylene, then Y is IN The object compound (I) or a salt thereof can be 10 prepared by processes as illustrated in the following reaction schemes.

Process 1 1 1 X CH2CO-Y-A-R (II) r2nh s \ II C=N-C-NH-) / z R NH (III) or a salt thereof or a salt thereof R2NH Nx c=n—ii JJ -Y-A-R R NH (I) or a salt thereof Process 2 R2NH n-—y-a-r; R3NH (1-1) or a salt thereof Elimination of the amino protective group - 4 IE 903216 R^NH N-r—Υ-ΝΉ. >NJ|J R3NH (1-2) or a salt thereof Process 3 R NH N-r—Y-A-NH Acylation C=N15 R3NH' S' (1-2) or a salt thereof R2NH -Υ-Α-ΐξ R3NH (1-3) or a salt thereof -5 Process 4 R2NH N-—Y-A-NH, Ra)2C=Z-R (IV) b R NH (1-2) or a salt thereof - 5 8 R2NH Z-R ii 7 N-t-Y-A-NHCR r3nhx (1-4) or a salt thereof Process 5 R2NH Z-R II 7 N-—Y-A-NHCR C=Nh-R^ (V) r3nh' (1-4) or a salt thereof R2NH Z-R II η N-rY-A-NHCR' R3NH (1-5) or a salt thereof Process 6 R2NH N-n-Y-A-NH. :=n— r3nh/ 2 R3 - Xz (VI) (1-2) or a salt thereof - 6 IE 903216 R2NH N-Y-A-NHR^ 0=nAJ Process 7 R2NH r3nh N— r3nh (1-6) or a salt thereof N-CN 11 7 -Y-A-NHC-R1 (1-7) or a salt thereof R2NH Nxc=N-i SJ / R NH Process 8 NH R2NH =nA J / R NH R10NHNH, (VII) NH, NII -Y-A-NH—U „.N ,10 (1-8) or a salt thereof Ring closure -coch2sc-a-r (VIII) or a salt thereof - 7 IE 903216 R NH z R NH =N-U L -N -A-R Process 9 R2NH N3 7 R NH C=N-coch2x(IX) or a salt thereof R2NH Process 10 R2NH N3 / R NH S(1-9) or a salt thereof / R NH N-CN II -Y-A-C-NH. (1-10) or a salt thereof h2n-c-a-r (X) or a salt thereof =N—ί „ J--A-R1 (1-9) or a salt thereof Hydrolysis - 8 IE 903216 C-CONH.

R2NH N-—Y-A-C-NH.

C=Nr3nh (1-11) or a salt thereof Process 11 r2nh r3nh \ Ii || N-,—Y-A-NH.

N-R R -CH (XI) (1-2) or a salt thereof N-R r2nh N-r-Y-A-NH-CH r3nh (1-12) or a salt thereof Process 12 RNH N-j-Y-A-CN r3nh x Rx OH (XII) (1-13) or a salt thereof - 9 R2NH NH II N-j-Y-A-C-OR c=Nz J r3nh (1-14) or a salt thereof Process 13 r2nh^ 3 R NH NH N-rY-A-C-ORJ NH2-R (XIII) (1-14) or a salt thereof R2NH N-R II -Y-A-C-NH R3NH (1-15) or a salt thereof Process 14 1 R S N--Y-A-R z * H2N H2N-Q-NH2 (XV) or a salt thereof (XIV) or a salt thereof - 10 IE 903216 Η ZN\ Qx /C N H N-r—Y-A-R (1-16) or a salt thereof Process 15 1 R S N-r—Y-A-R π-Γ:=n-£J NHO-R2 Z cl (XVII) 3 R NH (XVI) or a salt thereof r2nh a N--Y-A-R' R3NH (1-17) or a salt thereof Process 16 NH R2NH \ 3' R NH N-r—Y-A-C-OR Hydrolysis (1-14) or a salt thereof - 11 IE 903216 R2NH N-:—Y-A-CO2R13 r3nh (1-18) or a salt thereof Process 17 R NH NY-A-CO-R !i 2 Amidation ->R NH (1-18) or a salt thereof R2NH N-r—Y-A-CONH.

IN-Γ >N-O r3nh (1-19) or a salt thereof Process 18 R2NH -Y-A-CO2R Hydrazine X R NH (1-18) or a salt thereof - 12 r2nh N-r C=N—H. J rW Y-A-CONHNH. (1-20) or a salt thereof Process 19 R2NH 7 R'NH X =>UJ N--Y-A-CONHNH, S-(lower alkyl) isothiourea or a salt thereof (1-20) or a salt thereof NH R2NH r3nh N--Y-A-CONHNH-C-NH.

:=UlJ (1-21) or a salt thereof Process 20 NH R2NH , N-r-Y-A-CONHNH-C-NH. >NJiJ Ring closure / R NH (1-21) or a salt thereof - 13 IE 903216 R2NH r3nhz/ (1-22) or a salt thereof Process 21 R2NH N-j—Y-A-R kW (1-23) or a salt thereof R2NH r3nh^ Process 22 H„N „ . 2 N-Y-A-R H2N Elimination of the hydroxy protective group N-r—Y-A-Rj :=n-O (1-24) or a salt thereof Acylation -+ (1-25) or a salt thereof r£nh Y-A-R H2N (1-26) or a salt thereof Process 23 r2nh N-i—Y-A-CONH, Dehydration X R NH (1-19) or a salt thereof R2NH N-r :=N-4si) -Y-A-CN (1-27) or a salt thereof Process 24 R2NH N-j—Y-CO-R16 X Ii I 2 C=N-TcX / S R NH Reduction (1-28) or a salt thereof - 15 IE 903216 R NH , N-rY-CHnOH \ II I 2 C=N—k _> ,/ R NH (1-29) or a salt thereof Process 25 PNH N-—Y-A-OH 1' c=n-A / S R NH (1-30) or a salt thereof Halogenation ->R2NH r3nh (1-31) or a salt thereof Process 26 R2NH n-γ-υ-α-r; H-Rf (XVIII) -> r3nh' (1-31) or a salt thereof R2NH n-y-a-r1 ίο Process 27 r3nh Γ: or (1-321 a salt thereof ϊΓΝΗ^ N-—Y-CH^OH C= r3nhx N —Y-CH-C :=nAJ (1-29) or a salt thereof r2nh r3nhx c= or Oxidation Ν-:—Y-CHO (1-33) a salt thereof Process 28 Hydrolysis R2NH Y-A-CN / R NH (1-13) or a salt thereof - 17 IE 903216 R2NH NY-A-CONH.

:=N—L R NH (1-19) or a salt thereof Process 29 r2nh r3nh· NC=N-Y-A-R (1-31) or a salt thereof (XIX) R2NH . N-r—Y-A-R X R NH (1-34) or a salt thereof Process 30 R2NH N-y-a-r; η7ννη9·η2ο X RNH (1-34) or a salt thereof - 18 IE 903216 R2NH N-—Y-A-NHn :=n4J Process 31 r3nh r3nh (1-2) or a salt thereof R2NH Hydrogenation (1-35) or a salt thereof R2NH A-R 3 R NH (1-36) or a salt thereof Process 32 R2NH N-r-Y-A*h / R NH C=NElimination of the amino protective group -> (1-37) or a salt thereof - 19 IE 903216 R2NH k N--η-Υ-Α-Rt x || 1 C=N—k X R NET (1-38) or a salt thereof wherein R1, R2, R3, R4, R5, R6, Y and A are each as defined above, R1 is protected amino, al R, is acylamino, 1° R is acylamino having protected hydroxy, C1 R, is acylamino having hydroxy, la R is halogen, el Rt is heterocyclic thio, R is imido, Rf is acylamino having protected amino, ln R. is acylamino having ammo, R is lower alkyl which may have halogen, 2a is acyl, R6 is halogen, 7a R is lower alkylthio or protected hydroxy, a7 R' is amino which may have suitable o substituent (s), Q R is hydrogen, cyano, nitro or acyl, Q 1 R is suitable substituent in R as defined above, R1® is hydrogen or lower alkyl, R is protected hydroxy, R12 is acyl, R is lower alkyl, R is acyl or cyano, Ri0 is lower alkyl, R16 is lower alkyl, X1 is acid residue, X is acid residue or protected hydroxy, X is acid residue, - 20 IE 903216 Z is N or CH, Q is lower alkylene, and M is alkali metal.

In the above and subsequent descriptions of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.

The term lower is intended to mean a group having 1 to 6 carbon atom(s) preferably 1 to 4 carbon atom(s), unless otherwise provided.

Suitable lower alkoxy may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

Suitable lower alkylthio may include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, and the like.

Suitable acid residue may include halogen such as chloro, bromo, fluoro and iodo.

Suitable lower alkylene and lower alkylene moiety 2 3 formed by linkage of R and R may be straight or branched 25 one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and the like, in which the preferable one is C1~C4 alkylene and the most preferable one is methylene and ethylene.

Suitable amino which may have suitable 30 substituent (s) is conventional one used in a pharmaceutical field and may include amino, mono or di{lower)alkylamino (e.g. methylamino, dimethylamino, ethylamino, butylamino, etc.), lower alkenylamino (e.g. vinylamino, propenylamino, etc.), lower alkynylamino (e.g. ethynylamino, propynylamino, etc.), hydroxy(lower)- 21 903216 alkylamino (e.g. hydroxymethylamino, hydroxyethylamino, hydroxypropylamino, etc.), lower alkoxy(lower)alkylamino (e.g. methoxymethylamino, etc.), mono or di(lower)alkylamino(lower)alkylamino (e.g. methylaminomethylamino, dimethylaminoethylamino, etc.), protected amino such as acylamino, in which acyl is as mentioned below, heterocyclic amino, in which heterocyclic group is as mentioned below, cyclo(lower)alkenylamino which may have one or more, preferably one to three suitable substituent (s) such as amino and oxo [e.g. (l-amino-3,4-dioxo-l-cyclobuten-2-yl)amino), etc.], imino (e.g. succinimido, phthalimido, etc.), a group of the formula : -NHC-R Q wherein R and Z are each as defined above, and R is hydrogen, lower alkylthio, protected hydroxy or amino which may have suitable substituent (s), each of which is as mentioned above or below, and the like.

Suitable ’’lower alkyl’’ may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which the preferable one is C^-C^ alkyl and the more preferable one is methyl or ethyl.

Suitable ”acyl” and the acyl group in the term ’’acylamino’’ may include carbamoyl, thiocarbamoyl, sulfamoyl, an aliphatic acyl, an aromatic acyl, a heterocyclic acyl and an aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carbamic, - 22 IE 903216 sulfonic, carboxylic or carbonic acid, and their thio acids.

The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), (C^-C^)-cycloalkanecarbonyl (e.g. eyelopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, etc.), lower alkoxalyl (e.g. methoxalyl, ethoxalyl, etc.), lower alkanoylcarbonyl (e.g. pyruvoyl, etc.), and the like.

The aromatic acyl may include aroyl (e.g. benzoyl, nitrobenzoyl, toluoyl, xyloyl, etc.), arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the like.

The heterocyclic acyl may include heterocyclic carbonyl (e.g. furoyl, thenoyl, nicotinoyl, 1-oxonicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, morpholinocarbonyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group(s) may include phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), phenoxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.), and the like.

The aliphatic acyl substituted with heterocyclic group(s) may include thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolyl- 23 IE 903216 propionyl, and the like.

These acyl groups may be further substituted with suitable substituent(s) such as hydroxy, amino, guanidino carboxy, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), lower alkenyl (e.g. vinyl, allyl, etc.), halogen (e.g. chloro, bromo, iodo, fluoro), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), lower alkoxycarbonyl(lower)alkoxy (e.g. methoxycarbonylmethoxy, etc.), lower alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.), heterocyclic(lower)alkylthio (e.g. furylmethylthio, thiazolylmethylthio, etc.), heterocyclic (lower)alkylsulfinyl (e.g. furyImethyIsulfinyl, thiazolylmethylsulfinyl, etc.), nitro, acyl as mentioned above, protected amino in which the amino protective moiety may be the same as those herein, aryl (e.g. phenyl, etc.), aroyl (e.g. benzoyl, etc.), aryloxy (e.g., benzyloxy, tolyloxy, etc.), protected hydroxy such as acyloxy, for example, lower alkanoyioxy (e.g. formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, etc.), lower alkylamino (e.g. methylamino, dimethylamino, ethylamino, etc.), amino-protective group as aftermentioned, and the like, and the preferable acyl having such substituent(s) may be lower alkoxy(lower)alkanoyl (e.g., methoxyacetyl, ethoxyacetyl, etc.), lower alkanoyioxy!lower)alkanoyl (e.g., acetoxyacetyl, acetoxypropionyl, etc.), N-lower alkylcarbamoyl (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, etc.), aroylthiocarbamoyl (e.g. benzoylthiocarbamoyl, etc.), heterocyclic (lower)alkylthio(lower)alkanoyl (e.g. furylmethylthioacetyl, etc.), N-lower alkylthiocarbamoyl - 24 IE 903216 (e.g. N-methylthiocarbamoyl, etc.), halo(lower)alkanoyl (e.g. trifluoroacetyl, etc.), hydroxy(lower)alkanoyl (e.g. hydroxyacetyl, etc.), amino(lower)alkanoyl (e.g. aminoacetyl, etc.), lower alkylamino(lower)alkanoyl (e.g. dimethylaminoacetyl, etc.), lower alkylthio(lower)alkanoyl (e.g. methylthioacetyl, etc.), lower alkoxycarbonyl(lower) alkoxy(lower)alkanoyl (e.g. methoxycarbonylmethoxyacetyl, etc.), N-lower alkoxycarbonylamino(lower)alkanoyl (e.g.

N-t-butoxycarbonylaminoacetyl, etc.), lower alkyl(C^-C^)cycloalkanecarbonyl (e.g. methylcyclopropanecarbonyl, etc.), N-aminocarbamoyl, N-guanidinocarbamoyl, N-lower alkylsulfamoyl (e.g. N-methylsulfamoyl, · etc.).

Suitable heterocyclic group and heterocyclic moiety in the terms heterocyclic amino and heterocyclic thio may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur nitrogen atom and the like. Especially preferably heterocyclic group may be or 6-membered aromatic heteromonocyclic group (e.g. pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, etc.), 5- or 6-membered aliphatic heteromonocyclic group (e.g. morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, etc.), unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atom(s) (e.g. benzimidazolyl, etc.), unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g. benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, etc.), and the like. Thus defined heterocyclic moiety may have suitable substituent(s) such as amino, oxo, halogen as chloro, lower alkyl as defined above, and the like. Preferable example of such groups are triazolyl having amino and lower alkyl (e.g. 3-amino-l-methyl-lH-triazol- 25 IE 903216 -yl, etc.), triazolyl having amino (e.g. 3-amino-lH-triazolyl-5-yl, etc.), benzoisothiazolyl having oxo (e.g. 1,1-dioxobenzoisothiazolyl, etc.).

Suitable amino-protective group in the term 5 protected amino may include ar(lower) alkyl such as benzyl, benzhydryl, phenethyl and the like, and acyl as mentioned above.

Suitable hydroxy-protective group in the term protected hydroxy may include aforesaid acyl, ar(lower)alkyl (e.g. benzyl, trityl, etc.) lower alkoxy(lower)alkyl (e.g. methoxymethyl, 1-methyl-lmethoxyethyl, methoxypropyl, etc.), tetrahydropyranyl, aryl (e.g. phenyl, etc.), lower alkyl (e.g. methyl, ethyl, etc.), and the like.

Suitable halogen may be chloro, bromo, fluoro and iodo.

Suitable lower alkyl which may have halogen may include lower alkyl as mentioned above, mono or di or trihalo(lower) alkyl such as trifluoro(lower) alkyl (e.g. trifiuoromethyl, trifluoroethyl, etc.), and the like.

Suitable imido may include succinimido, phthalimido, and the like.

Suitable acylamino having protected hydroxy may include acylamino as mentioned above which is substituted by a protected hydroxy as exemplified above, for example, protected hydroxy(lower)alkanoylamino such as lower alkanoyloxy(lower)alkanoylamino (e.g. acetoxyacetylamino, etc.), and the like.

Suitable acylamino having hydroxy may include acylamino as mentioned above which is substituted by hydroxy, for example, hydroxy(lower)alkanoylamino (e.g. hydroxyacetylamino, etc.), and the like.

Suitable acylamino having protected amino may include acylamino as mentioned above which is substituted by a protected amino as exemplified above, for example, protected amino(lower)alkanoylamino such as lower alkoxycarbonylamino(lower)alkanoylamino (e.g. t-butoxycarbonylaminoacetylamino, etc.), and the like.

Suitable acylamino having amino may include 5 acylamino as mentioned above which is substituted by amino, for example, amino(lower)alkanoylamino (e.g. aminoacetylamino, etc.), and the like.

Suitable alkali metal may include sodium, potassium, and the like.

Suitable lower alkylthioureido may include 3-lower alkylthioureido (e.g. 3-methylthioureido, etc.), and the like.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], a salt with an acidic amino acid [e.g. aspartic acid salt, glutamic acid salt, etc.], and the like.

With respect to the salt of the compounds (1-1) to (1-38), (II), (III), (VIII), (IX), (X), (XIV), (XV) and (XVI) in the Processes 1 to 32, it is to be noted that these compounds are included within the scope of the compound (I), and accordingly the suitable examples of the salts of these compounds are to be referred to those as exemplified for the object compound (I). 2 Particularly, the preferred embodiments of R , R , R3, R^, r5, r6, γ and A are as follows.

R1 is amino, mono or di(lower)alkylamino (e.g. dimethylamino, etc.), acylamino, for example, ureido, lower alkanoylamino (e.g. formylamino, acetylamino, - 27 IE 903216 propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, etc.), lower alkoxycarbonylamino (e.g. methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, etc.), lower alkylsulfonylamino (e.g. mesylamino, etc.), lower alkoxy(lower)alkanoylamino (e.g. methoxyacetylamino, etc.), mono or di or trihalo(lower)alkanoylamino (e.g. trifluoroacetylamino, etc.), hydroxy(lower)alkanoylamino (e.g. hydroxyacetylamino, etc.), protected hydroxy(lower)alkanoylamino such as lower alkanoyloxy(lower)alkanoylamino (e.g. acetoxyacetylamino, acetoxypropionylamino, etc.), amino(lower)alkanoylamino (e.g. aminoacetylamino, etc.), protected amino(lower)alkanoylamino such as lower alkoxycarbonylamino(lower)alkanoylamino (e.g. t-butoxycarbonylaminoacetylamino, etc.), lower alkoxycarbonyl(lower) alkoxy(lower)alkanoylamino (e.g. methoxycarbonylmethoxyacetylamino, etc.), lower 0 alkylthio(lower)alkanoylamino (e.g. methylthioacetylamino, etc.), lower alkanoyl(lower)alkanoylamino (e.g. acetylpropionylamino, etc.), mono or di(lower)alkylamino (lower) alkanoylamino (e.g. dimethylaminoacetylamino, etc.), heterocyclic (lower)alkylthio(lower)alkanoylamino such as 5- or 6- membered heteromonocyclic(lower )alkylthio(lower)alkanoylamino (e.g. furyImethylthioacetylamino, etc.), lower alkylureido such as 3-lower alkylureido (e.g. 3-methylureido, 3-ethylureido, 3-propylureido, 3-isopropylureido, etc.), lower alkylthioureido such as 3-lower alkylthioureido (e.g. 3-methylthioureido, etc.), cyclo(lower)alkanecarbonylamino (e.g. cyclopropanecarbonylamino, cyclopentanecarbonylamino, - 28 IE 903216 cyclohexanecarbonylamino, eyeloheptanecarbonylamino, etc.), lower alkylcyclo(lower)alkanecarbonylamino (e.g. methylcyclopropanecarbonylamino, etc.), heterocycliccarbonylamino such as 5- or 6-membered heteromonocycliccarbonylamino (e.g. furoylamino, nicotinoylamino, etc.), cyclo(lowerJalkenylamino having amino and oxo (e.g. aminodioxocyclobutenylamino, etc.), imido (e.g. phthalimido, etc.), heterocyclic amino, for example, optionally benzene-fused 5- or 6-heteromonocyclic amino which may be substituted by one or more substituent (s) selected from the group consisting of lower alkyl, amino and oxo such as triazolylamino substituted by amino (e.g. 3-aminotriazolylamino, etc.), triazolylamino substituted by amino and lower alkyl (e.g. 3-amino-1-methyltriazolylamino, etc.) and benzoisothiazolylamino substituted by oxo (e.g. 1,1-dioxobenzoisothiazolylamino, etc.), 2-cyano-3-lower alkylguanidino (e.g. 2-cyano-3-methylguaidino, etc.), 2-lower alkanesulfonyl-3-lower alkylguanidino (e.g. 2-methanesulfonyl-3-methylguanidino, etc.), 2-lower alkanesulfonylguanidio (e.g. 2-ethanesulfonylguanidino, etc.), (1-lower alkylamino-2-nitrovinyl)amino (e.g. (1-methylamino-2-nitrovinyl)amino, etc.); hydroxy; halogen (e.g. chloro, etc.); cyano; acyl such as carbamoyl, aminocarbamoyl, guanidinocarbamoyl, lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.) and lower alkanoyl (e.g. formyl, etc.); heterocyclic thio such as unsaturated condensed heterocyclic thio containing 1 to 3 nitrogen atom(s) - 29 IE 903216 (e-g benzimidazolylthio, etc.); heterocyclic group, for example, 5- or 6-membered heteromonocyclic group such as triazolyl substituted with amino (e.g. 3-aminotriazolyl, etc.); or a group of the formula : N-R -C-R' R' in which R is hydrogen; cyano; or acyl such as carbamoyl, sulfamoyl, lower alkylsulfonyl (e.g. mesyl, etc.), and mono or di (lower)alkylsulfamoyl (e.g. methylsulfamoyl, etc.); and _5 .

R is ammo; or lower alkoxy (e.g. methoxy, etc.); is hydrogen; acyl such as lower alkylcarbamoyl (e.g. methylcarbamoyl, etc.); lower alkyl which may have halogen such as lower alkyl (e.g. methyl, etc.), mono or di or trihalo(lower)alkyl (e.g. trifluoroethyl, etc.); is hydrogen; or and R are linked together to form lower alkylene (e.g ethylene, etc.); r,6 Y is N or —{j- -j}— , in which R^ is hydrogen or halogen (e.g. chloro, etc.); and A is bond; or lower alkylene (e.g. methylene, ethylene, etc.); provided that when RX is amino which may have suitable substituent (s) and A is bond; or R^ is lower alkylthioureido and A is lower alkylene, then Y is N in which R^ is as defined above.

The processes for preparing the object compounds (I) of the present invention are explained in detail in the following.

Process 1 : The object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.

This reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as methyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetone, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dioxane, water, alcohol [e.g. methanol, ethanol, etc.] acetic acid, formic acid, etc. or a mixture thereof.

The reaction temperature is not critical and the reaction is usually conducted under cooling to heating.

Process 2 The object compound (1-2) or a salt thereof can be prepared by subjecting the compound (1-1) or a salt thereof to elimination reaction of the amino protective group.

Suitable method for this elimination reaction may include conventional one such as hydrolysis, reduction, or the like. The hydrolysis is preferably carried out in the presence of a base or an acid. - 31 IE 903216 Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), ammonia, or the like, and an organic base such as tri (lower)alkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0}non-5-one, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]undecene-5 or the like. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

The present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 3 The object compound (1-3) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with an acylating agent. - 32 IE 903216 The compound (1-2) may be used in the form of its conventional reactive derivative at the amino group.

The acylating agent can be represented by the compound of the formula : R17 - OH (XXI) in which R is acyl as defined above and its conventional reactive derivative at the hydroxy group.

The suitable example may be an acid halide (e.g. acid chloride, etc.), an acid anhydride, an activated amide, an activated ester, and the like.

In this reaction, when the compound (XXI) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as 1-(3-dimethylaminopropyl)-3ethylcarbodiimide, and the like.

In case the acyl group to be introduced is a carbamoyl type acyl, the acylating agent is usually used in the form of cyanate or isocyanate.

The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.] acetone, dioxane, acetonitrile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, pyridine, acetic acid or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri (lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N,N-di(lower) alkylbenzylamine, or the like.

This present reaction includes, within its scope, the 2 . . . case that when R is hydrogen, it is also acylated during the reaction or at the post-treating step of the present process.

Process 4 The object compound (1-4) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof with the compound (IV).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

The object compound (1-4) can be used as a starting 20 compound of Process 5 or Process 7 mentioned hereinbelow with or without isolation.

Process 5 The object compound (1-5) or a salt thereof can be 25 prepared by reacting the compound (1-4) or a salt thereof with the compound (V).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

In case that the compound (V) is liquid, it can be also used as a solvent.

The reaction temperature is not critical, and the 35 reaction is usually carried out at ambient temperature or - 34 IE 903216 under warming or heating.

Process 6 The object compound (1-6) or a salt thereof can be 5 prepared by reacting the compound (1-2) or a salt thereof with the compound (VI).

The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, pyridine or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine, N-(lower)alkylmorphorine, N,N-di (lower) alkylbenzylamine, or the like.

Process 7 The object compound (1-8) or a salt thereof can be prepared by reacting the compound (1-7) or a salt thereof with the compound (VII).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating. - 35 IE 903216 Process 8 The object compound (1-9) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to ring closure.

This reaction is usually carried out in the presence of ammonium hydride.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating, preferably under heating.

Process 9 The object compound (1-9) or a salt thereof can be prepared by reacting the compound (IX) or a salt thereof with the compound (X) or a salt thereof.

This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.

Process 10 The object compound (I—11) or a salt thereof can be prepared by subjecting the compound (1-10) or a salt thereof to hydrolysis reaction.

This reaction is usually carried out in a conventional manner for transforming nitrile to amide.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, - 36 IE 903216 dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 11 The object compound (1-12) or a salt thereof can be prepared by reacting the compound (1-2) or a salt thereof Ϊ0 with the compound (XI).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 12 The object compound (1-14) or a salt thereof can be prepared by reacting the compound (1-13) or a salt thereof with the compound (XII).

This reaction is usually carried out in the presence 25 of dry hydrogen chloride gas.

This reaction is usually carried out in a conventional solvent such as alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν,Ν-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

The object compound (1-14) can be used as a starting - 31 IE 903216 compound of Process 16 mentioned hereinbelow with or without isolation.

Process 13 The object compound (1-15) or a salt thereof can be prepared by reacting the compound (1-14) or a salt thereof with the compound (XIII).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, 2-methoxyethanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 14 The object compound (1-16) or a salt thereof can be prepared by reacting the compound (XIV) or a salt thereof with the compound (XV) or a salt thereof.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 15 The object compound (1-17) or a salt thereof can be prepared by reacting the compound (XVI) or a salt thereof with the compound (XVII) or a salt thereof.

This reaction can be carried out in substantially the - 38 IE 903216 same manner as Process 5, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 5.

Process 16 The object compound (1-18) or a salt thereof can be prepared by subjecting the compound (1-14) or a salt thereof to hydrolysis.

This reaction is usually carried out in a conventional solvent such as a mixture of water and alcohol [e.g. methanol, etc.] or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 17 The object compound (1-19) or a salt thereof can be prepared by subjecting the compound (1-18) or a salt thereof to amidation.

This reaction is usually carried out in the presence of ammonia.

This reaction is usually carried out in a conventional solvent such as alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν,Ν-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 18 The object compound (1-20) or a salt thereof can be prepared by reacting the compound (1-18) or a salt thereof with hydrazine. - 39 IE 903216 This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 19 The object compound (1-21) or a salt thereof can be prepared by reacting the compound (1-20) or a salt thereof with S-(lower alkyl)isothiourea or a salt thereof.

This reaction is usually carried out in a 15 conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the 20 reaction is usually carried out at ambient temperature or under warming or heating.

Process 20 The object compound (1-22) or a salt thereof can be 25 prepared by subjecting the compound (1-21) or a salt thereof to ring closure.

This reaction is usually carried out in the presence of ammonium hydroxide.

This reaction is usually carried out in a 30 conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the 35 reaction is usually carried out at ambient temperature or - 40 IE 903216 under warming or heating.

Process 21 The object compound (1-24) or a salt thereof can be 5 prepared by subjecting the compound (1-23) or a salt thereof to elimination reaction of the hydroxy-protective group.

This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 2.

Process 22 The object compound (1-26) or a salt thereof can be prepared by reacting the compound (1-25) or a salt thereof with an acylating agent.

This reaction can be carried out in substantially the same manner as Process 3, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 3.

This present reaction includes, within its scope, the case that when R1 is amino, it is also acylated during the reaction or at the post-treating step of the present process.

Process 23 The object compound (1-27) or a salt thereof can be prepared by subjecting the compound (1-19) or a salt thereof to dehydration reaction.

The dehydrating agent to be used in this dehydration reaction may include phosphoryl chloride, thionyl chloride, phosphorus pentoxide, phosphorus pentachloride, phosphorus pentabromide and the like. - 41 This present reaction is usually carried out in a solvent such as dioxane, chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent which 5 does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, under warming or heating.

Process 24 The object compound (1-29) or a salt thereof can be prepared by subjecting the compound (1-28) or a salt thereof to reduction.

The reduction may include, for example, reduction 15 with an alkali metal borohydride (e.g. sodium borohydride, etc.), and the like.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 25 The object compound (1-31) or a salt thereof can be prepared by subjecting the compound (1-30) or a salt thereof to halogenation.

This reaction is usually carried out in a 30 conventional manner for transforming hydroxy to halogen, preferably by using thionyl chloride.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl - 42 IE 903216 sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 26 The object compound (1-32) or a salt thereof can be prepared by reacting the compound (1-31) or a salt thereof with the compound (XVIII).

The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, pyridine or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate (e.g. potassium carbonate, etc.), tri (lower)alkylamine (e.g. triethylamine, etc.), pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.

Process 27 The object compound (1-33) or a salt thereof can be prepared by subjecting the compound (1-29) or a salt thereof to oxidation.

This reaction is usually carried out in a conventional manner for transforming hydroxymethyl to formyl, for example, by using pyridinium dichromate.

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, - 43 IE 903216 propanol, etc.], tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating, preferably under cooling.

Process 28 The object compound (1-19) or a salt thereof can be prepared by subjecting the compound (1-13) or a salt thereof to hydrolysis reaction.

This reaction can be carried out in substantially the same manner as Process 10, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 10.

Process 29 The object compound (1-34) or a salt thereof can be 20 prepared by reacting the compound (1-31) or a salt thereof with the compound (XIX).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 30 The object compound (1-2) or a salt thereof can be prepared by reacting the compound (1-34) or a salt thereof with hydrazine hydrate. - 44 IE 903216 This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

The object compound (1-2) can be used as a starting 10 compound of Process 3 mentioned above with or without isolation.

Process 31 The object compound (1-36) or a salt thereof can be 15 prepared by subjecting the compound (1-35) or a salt thereof to hydrogenation.

The method applicable for this reaction may include, for example, conventional catalytic reduction in the presence of a conventional metallic catalyst (e.g. palladium on carbon, etc.).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e.g. methanol, ethanol, propanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, Ν,Ν-dimethylformamide or a mixture thereof.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.

Process 32 The object compound (1-38) or a salt thereof can be prepared by subjecting the compound (1-37) or a salt thereof to elimination reaction of the amino protective group.

This reaction can be carried out in substantially the - 45 IE 903216 same manner as Process 2, and therefore the reaction mode and reaction conditions [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 2.

Among the starting compounds, some of them are new and such compounds can be prepared by the methods of Preparation mentioned below and by any process known in the art for preparing structurally analogous compounds thereto.

The compounds obtained by the above Processes 1 to 32 can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation or the like.

It is to be noted that each of the object compound (I) may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.

The new thiazole derivatives (I) and pharmaceutically acceptable salts thereof possess antiulcer activity and H2-receptor antagonism, and are useful for a therapeutic treatment of gastritis, ulcer (e.g. gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.), Zollinger-Ellison Syndrome, reflux esophagitis, upper gastrointestinal bleeding, and the like.

And further, the compound (I) and pharmaceutically acceptable salts thereof of the present invention possess high antimicrobial activity against pathogenic microorganisms such as Campylobacter pyloridis, which is a gram-negative bacillus that has recently been found beneath the mucus gel of the human stomach.

For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present - 46 IE 903216 invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, inadmixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral or parenteral administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solution, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average singel dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating ulcer. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

In order to illustrate the usefulness of the object compound (I), the pharmacological test data of some representative compounds of the compound (I) are shown in the following.

Test compounds (a) 4-(6-Acetylaminomethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole dihydrochloride (b) 2-(Diaminomethyleneamino)-4-(6-ureidomethylpyridin2-yl) thiazole dihydrochloride (c) 2-(Diaminomethyleneamino)-4-{2-ureidomethylthiazol4-yl)thiazole (d) 4-[2-(Diaminomethyleneamino)thiazol-4-yl]thiazole2-carboxylic acid ethyl ester hydrobromide - 47 IE 903216 Test A (Gastric secretion in Heidenhain pouch dogs) : Test Method Beagle dogs, weighing about 8-13 kg, were used for 5 the study on gastric secretion. The animals were surgically provided with a vagally denervated Heidenhain pouch. One month or more later, the dogs were fasted overnight. Gastric secretion was stimulated by an intravenous infusion of tetragastrin (10 pg/kg/hr).

Gastric samples were collected at 15 min intervals. After its volume was almost constant, test compound (3.2 mg/kg) suspended in 0.1% methyl cellulose solution was administered orally. Acid concentration was determined by titrating an aliquot to pH 7.0 with 0.1N sodium hydroxide solution using automatic titration (Hiranuma RAT-11 Type). Total acid output was calculated by multiplying total volume of gastric samples by acid concentration, and percentage change of total acid output was calculated by comparing with predosing value of test compound.

Test Result Test Compound Inhibition (%) (a) 95 Test B (Inhibition of stress ulcer) : Test Method Five male Sprague-Dawley rats, aged 7 weeks and weighing about 200 g were used per group for the study on stress ulcer after the fast for 24 hours. Each animal was immobilized in a restrain cage and immersed to a level of the xiphoid in a water bath kept 22°C. Each of the test - 48 IE 903216 compounds (32 mg/kg) suspended in 0.1% methylcellulose solution was administered orally just before the immobilization. Seven hours later, the animals were sacrificed and their stomachs were removed. The stomach was then fixed with 2% formalin. The area of ulcers was measured for each animal, and percentage of inhibition was 2 calculated by comparing the mean area of ulcers (mm ) in the test animals with that in the control animals.

Test Result Test Compound Inhibition (%) (d) 93.9 Test C (Gastric secretion from lumen perfused stomach in anesthetized rats) : 2θ Test Method Male Sprague-Dawley rats weighing about 250 g were used. Rats were deprived of food but allowed free access to water for 24 hours. The animals were anesthetized with 1.25 g/kg urethane intraperitoneally. The abdomen was 25 opened and the gastric lumen was perfured with saline throughout the experiment. The perfusate was titrated by an antotitrator with 25 mM sodium hydroxide as a titrant. Gastric secretion was stimulated by intravenous infusion with histamine (3 mg/kg/hr). After reaching plateau, test compound (1 mg/kg) was given intravenously. Drug effect was expressed as maximal inhibition by acid output. - 49 IE 903216 Test Result Test Compound Inhibition (%) (b) 98 (c) 97 Test D (Anti-microbial activity) : Test Method In vitro antimicrobial activity was determined by the agar dilution method. Test strain was precultured in Brucella broth containing 5% horse serum at 37°C for 3 days 10 cfu were inoculated with a multipoint replicater onto Brucella agar plus 5% lysed horse blood plate containing serial 2-fold dilutions of each drug at 37°C for 3 days. Incubation was carried out in an atmosphere of 10% CC>2 · MIC was read after incubation as the lowest drug concentration that inhibited macroscopic colonial growth.

Test Result Mic (pg/ml) Test Compound Test strain ’------- (a) Campylobacter pyloridis 8008 3.13 The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.

Preparation 1 Phosphorus oxychloride (7.09 ml) was added dropwise to a solution of 6-hydroxymethyl-2-pyridinecarboxamide (3.60 g) in Ν,Ν-dimethylformamide (36 ml) at 0 to 5°C with stirring and the mixture was stirred for further 6 hours at the same temperature.

The solvent was evaporated in vacuo and the residue was dissolved in water (100 ml). The solution was made basic with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo to give 6-chloromethyl-2-pyridinecarbonitrile (3.02 g). mp : 61-63°C IR (Nujol) : 2240 cm1 NMR (DMSO-d6, δ) : 4.87 (2H, s), 7.90 (IH, dd, J=1.2Hz and 7.7Hz), 8.03 (IH, dd, J=1.2Hz and 7.7Hz), 8.14 (IH, t, J=7.7Hz) Preparation 2 A mixture of 6-chloromethyl-2-pyridinecarbonitrile (2.75 g) and potassium phthalimide (3.35 g) in Ν,Ν-dimethylformamide (27.5 ml) was stirred at ambient temperature for 4 hours. After the solvent was evaporated in vacuo, water (50 ml) was added to the residue and the resulting precipitate was collected by filtration to give 6-phthalimidomethyl-2-pyridinecarbonitrile (4.60 g). mp : 200-201°C IR (Nujol) : 2250, 1775, 1715 cm1 NMR (DMSO-d6, δ) : 4.99 (2H, s), 7.81 (IH, dd, J=1.0Hz and 7.7Hz), 7.85-7.98 (5H, m), 8.06 (IH, t, J=7.7Hz) Preparation 3 A solution of hydrazine hydrate (0.77 g) in methanol (5 ml) was added dropwise to a suspension of 6-phthalimidomethyl-2-pyridinecarbonitrile (3.74 g) in a mixture of methanol (10 ml) and tetrahydrofuran (15 ml) at ambient temperature with stirring. After the mixture was stirred for two hours, diluted hydrochloric acid (prepared by concentrated hydrochloric acid (1.38 ml) and water (6.91 ml)) was dropped to the mixture. After stirring for three hours, the solvent was evaporated in vacuo. The residue was mixed with water (20 ml) and an insoluble material was filtered off. The filtrate was evaporated in vacuo to give 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.40 g). mp : >300°C IR (Nujol) : 2240 cm1 NMR (DMSO-dg, δ) : 4.27 (2H, s), 7.94 (1H, dd, J=1.2Hz and 7.7Hz), 8.08 (1H, dd, J=1.2Hz and 7.7Hz), 8.16 (1H, t, J=7.7Hz), , 8.83 (3H, br s) Preparation 4 Acetic anhydride (1.29 ml) was added dropwise to a mixture of 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (2.10 g) in pyridine (21 ml). The solution was stirred for four hours at ambient temperature and evaporated in vacuo. The residue was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo to give 6-(acetylaminomethyl)-2-pyridinecarbonitrile (1.72 g). mp : 91-92°C IR (Nujol) : 3260, 2230, 1650 cm1 NMR (DMSO-dg, δ) : 1.92 (3H, s), 4.39 (2H, d, J=6Hz), 7.62 (1H, dd, J=lHz and 7.7Hz), 7.97 (1H, dd, J=lHz and 7.7Hz), 8.03 (1H, t, J=7.7Hz), 8.56 (1H, t, J=6Hz) Preparation 5 An ethereal solution of methyl magnesium bromide (3 mol/£) (17.6 ml) was added dropwise to a solution of 6-(acetylaminomethyl)-2-pyridinecarbonitrile (3.70 g) in tetrahydrofuran (60 ml) at 5 to 10°C with stirring. After the mixture was stirred for two hours at the same temperature, cold water (15 ml) was dropped to the mixture under ice-cooling and evaporated in vacuo. The residue was mixed with water and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography by eluting with a mixture of ethyl acetate and methanol (50:1) to give 2-acetyl-6-(acetylaminomethyl)pyridine (2.70 g). mp : 88-89°C IR (Nujol) : 3300, 1690, 1650 cm-1 NMR (DMSO-dg, δ) : 1.94 (3H, s), 2.64 (3H, s), 4.43 (2H, d, J=6.0Hz), 7.54 (IH, dd, J=lHz and 7.7Hz), 7.82 (IH, dd, J=lHz and 7.7Hz), 8.00 (IH, t, J=7.7Hz), 8.53 (IH, t, J=6Hz) Preparation 6 A solution of bromine (1.56 g) in acetic acid (5 ml) was added dropwise to a solution of 2-acetyl-6(acetylaminomethyl)pyridine (1.87 g) and 30 weight % hydrogen bromide-acetic acid solution (4.2 ml) in a mixture of acetic acid (40 ml) and methanol (10 ml) at ambient temperature with stirring. The mixture was warmed to 60 to 70°C and stirred for two hours. The solvent was evaporated in vacuo and the residue was triturated with diisopropyl ether to give 2-(acetylaminomethyl)-6-bromoacetylpyridine hydrobromide (3.78 g).

IR (Nujol) : 1720, 1620 cm'1 NMR (CD3OD, δ) : 2.10 (3H, s), 3.90 (2H, s), 4.83 (2H, s), 7.77 (1H, br s), 8.13 (2H, t, J=8Hz) and 8.70 (1H, t, J=8Hz) Preparation 7 A mixture of 2-bromo-l-hydroxy-3-oxo-l-butene (9.61 g) and N-[(thiocarbamoyl)methyl]acetamide (7.70 g) in acetone (100 ml) was refluxed for one hour with stirring. The resulting precipitate was collected by filtration and chromatographed on silica gel eluting with a mixture of chloroform and methanol (20:1, V/V) to give -acetyl-2-(acetylaminomethyl)thiazole (3.48 g). mp : 98-100°C IR (Nujol) : 3310, 1655 cm-1 NMR (DMSO-dg, δ) : 1.92 (3H, s), 3.55 (3H, s), 4.53 (2H, d, J=6Hz), 8.50 (1H, s), 8.83 (1H, t, J=6Hz) MS (m/e) : 198, 155 Preparation 8 A solution of bromine (1.61 g) in acetic acid (4 ml) was added dropwise to a mixture of 5-acetyl-2-acetylaminomethylthiazole (2.00 g), 30 (W/W) % hydrobromic acid solution in acetic acid (5 ml) and acetic acid (40 ml) at ambient temperature. After stirring for 24 hours at ambient temperature, the resulting precipitate was collected by filtration and washed with acetic acid to give 2-(acetylaminomethyl)-5-bromoacetylthiazole (3.00 g) mp : 160-164°C IR (Nujol) : 3250, 1700, 1655 cm 1 NMR (CD-jOD, δ) : 2.02 (3H, s) , 4.59 (2H, s), 4.69 (2H, s), 8.52 (1H, s) Preparation 9 A suspension of l-bromo-2,3-butanedione (47 g) and N-[(thiocarbamoyl)methyl]acetamide (30 g) in acetone (600 ml) was refluxed for 3 hours. The resulting precipitate was collected by filtration to afford 4-acetyl-2-(acetylaminomethyl)thiazole (41.8 g). mp : 185-186°C IR (Nujol) : 3410, 3350, 1690, 1620 cm'1 NMR (DMSO-dg, δ) ; 1.93 (3H, s), 2.55 (3H, s), 4.54 (2H, d, J=5.8Hz), 8.44 (IH, s), 8.91 (IH, t, J=5.8Hz) Preparation 10 A suspension of 4-acetyl-2-thiazolecarboxylic acid ethyl ester (2.5 g) in 28% aqueous ammonia solution (40 ml) was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration to afford 4-acetyl-2-thiazolecarboxamide (1.76 g).

NMR (DMSO-dg, δ) : 2.63 (3H, s), 8.02 (IH, s), 8.28 (1H, s), 8.74 (1H, s), Preparation 11 Bromine (9.9 ml) was added dropwise to a mixture of 2-acetyl-6-(acetylaminometyl)pyridine (37.0 g) in dioxane (740 ml) and 4N-dioxanic hydrogen chloride (48.1 ml) at ambient temperature with stirring. After the mixture was stirred at 50°C for 3 hours. To the mixture was added a diisopropyl ether (600 ml) and the mixture was stirred under ice-cooling for 30 minutes. The isolated precipitate was collected by filtration. The precipitate was added to water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The aqueous mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo to give 2-(acetylaminomethyl)-6-bromoacetylpyridine (50.3 g) as an oil.

TP. (Film) : 1710, 1650 cm NMR (CDC13, δ) : 2.11 (3H, s), 4.63 (2H, d, J=5.3Hz), 4.80 (2H, s), 7.43-7.59 (IH, m), 7.78-8.08 (2H, m) Preparation 12 Propionic anhydride (76.3 ml) was added dropwise to a mixture of 6-aminomethyl-2-pyridinecarbonitrile hydrochloride (84.1 g) in water (800 ml) under keeping pH 7~8 with 40% aqueous potassium carbonate at ambient temperature and the mixture was stirred at the same temperature for 30 minutes. The aqueous mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to give 6-(propionylaminomethyl)-2-pyridinecarbonitrile (54.2 g).

IR (Film) : 3280, 2240, 1640, 1590, 1535 cm-1 NMR (DMSO-dg, δ) : 1.05 (3H, t, J=7.6Hz), 2.21 (2H, q, J=7.6Hz), 4.40 (2H, d, J=5.8Hz), 7.61 (IH, dd, J=1.0Hz, 7.8Hz), 7.91 (IH, dd, J=1.0Hz, 7.8Hz), 8.03 (IH, t, J=7.8Hz), 8.50 (IH, t, J=5.8Hz) Preparation 13 The following compound was obtained according to a similar manner to that of Preparation 5. 2-Acetyl-6-(propionylaminomethyl)pyridine mp : 79°C IR (Nujol) : 3280, 1700, 1640, 1590, 1550 cm1 NMR (DMSO-dg, δ) : 1.06 (3H, t, J=7.6Hz), 2.22 (2H, q, J=7.6Hz), 2.64 (3H, s), 4.44 (2H, d, J=6.0Hz), 7.52 (IH, d, J=7.6Hz), 7.82 (IH, d, J=7.6Hz), 7.96 (IH, t, J=7.6Hz), 8.45 (IH, t, J=6.0Hz) Preparation 14 The following compound was obtained according to a similar manner to that of Preparation 11. 2-Bromoacetyl-6-(propionylaminomethyl)pyridine mp : 81-83°C IR (Nujol) : 3390, 1720, 1645 cm1 NMR (DMSO-d6' 6) : 1.06 (3H, t, J=7.6Hz), 2.22 (2H, q, J=7.6Hz), 4.44 (2H, d, J=5.9Hz), 5.05 (2H, s), , 7.57 (1H, d, J=7.6Hz), 7.89 (1H, d, J=7.6Hz), 8.01 (1H, t, J=7.6Hz), 8.45 (1H, t, J=5.9Hz) Preparation 15 A suspension of 2-(diaminomethyleneamino)-4bromoacetylthiazole (10.0 g) and N-[(thiocarbamoylimethyl)acetamide (5.0 g) in ethanol (100 ml) was stirred at room temperature for 10 hours. The resulting precipitate was collected by filtration to afford 4-[(2-acetylamino-l-iminoethyl)thioacetyl]-2(diaminomethyleneamino)thiazole hydrobromide (11.4 g).

IR (Nujol) : 3120, 1680, 1620 cm-1 NMR (DMSO-dg, δ) : 1.88 (3H, s), 3.37 (1H, d, J=12.0Hz), 3.64 (1H, d, J=12.0Hz), 4.03 (1H, dd, J=6.0 and 16.7Hz), 4.14 (1H, dd, J=6.0 and 16.7Hz), 6.90 (1H, s), 7.21 (1H, s), 8.19 (4H, s), 8.55 (1H, t, J=6.0Hz), 11.97 (1H, br) Preparation 16 A mixture of 2-chloromethyl-6-cyanopyridine (4.5 g), dimethylamine hydrochloride (7.2 g) and triethylamine (12.3 ml) in dichloromethane (70 ml) was stirred for 2.5 hours at ambient temperature and then the solvent was removed by concentration in vacuo. To the residue was added a mixture of ethyl acetate and tetrahydrofuran, washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V).

The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-cyano-6-(dimethylaminomethyl)pyridine (2.49 g) as an oil.

IR (Film) : 2240, 1585 cm-1 NMR (DMSO-dg, δ) : 2.20 (6H, s), 3.57 (2H, s), 7.77 (1H, dd, J=1.2Hz and 7.7Hz), 7.93 (1H, dd, J=1.2Hz and 7.7Hz), 8.04 (1H, t, J=7.7Hz) Preparation 17 The following compound was obtained according to a similar manner to that of Preparation 5. 2-Acetyl-6-(dimethylaminomethyl)pyridine IR (Film) : 3380, 1690, 1585 cm-1 NMR (DMSO- -dg, δ) : 2.23 (6H, s), 2.62 (3H, s), 3.62 (2H, s), 7.68 (1H, dd, J=l.lHz and 7.6Hz), 7.84 (1H, dd, J=l.lHz and 7.6Hz), 7.97 (1H, t, J=7.6Hz) 25 Preparation 18 A mixture of 6-hydroxymethyl-2-pyridinecarboxamide (100 g) and manganese dioxide (500 g) in chloroform (2 £.) was heated under reflux for 48 hours. Manganese dioxide was removed by filtration and the filtrate was evaporated in vacuo to give 6-formyl-2-pyridinecarboxamide (60.46 g) mp : 180-181°C IR (Nujol) : 3420, 3180, 1700 cm-1 NMR (DMSO-dg, δ) : 7.90 (1H, s), 8.10 (1H, dd, J=1.6Hz and 7.5Hz), 8.24 (1H, t, J=7.5Hz), 8.24-8.39 (1H, m), 8.32 (1H, dd, J=1.6Hz and 7.5Hz), 10.04 (1H, s) Preparation 19 An ethereal solution of methyl magnesium bromide (3 mol/£) (546 ml) was added dropwise to a solution of 6-formyl-2pyridinecarboxamide (61.5 g) in tetrahydrofuran (900 ml) at 0-13°C with stirring. After the mixture was stirred at the same temperature for 2 hours and cold water was dropped to the reaction mixture under ice-cooling. To the mixture was added ethyl acetate and adjusted to pH 7 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 6-(1-hydroxyethyl)-2-pyridinecarboxamide (63.2 g) as an oil.

IR (Film) : 3450-3200 (br), 1700-1650 (br) cm1 NMR (DMSO-dg, δ) : 1.42 (3H, d, J=6.5Hz), 4.73-4.86 (IH, m), 5.46 (IH, d, J=5.3Hz), 7.63-8.34 (5H, m) Preparation 20 The following compound was obtained according to a similar manner to that of Preparation 18. 6-Acetyl-2-pyridinecarboxamide mp : 143-145°C IR (Nujol) : 3180, 1680, 1590 cm1 NMR (DMSO-dg, δ) : 2.78 (3H, s), 7.88 (IH, s), 8.10 (IH, dd, J=1.7Hz and 7.5Hz), 8.19 (IH, t, J=7.5Hz), 8.28 (IH, dd, J=1.7Hz and 7.5Hz), 8.32 (IH, s) Preparation 21 The following compound was obtained according to a similar manner to that of Preparation 11. 6-Bromoacetyl-2-pyridinecarboxamide mp : 168-170°C IR (Nujol) : 3440, 1670, 1640, 1580 cm ‘ NMR (DMSO-dg, δ) : 5.35 (2H, s), 7.85 (1H, s), 8.15 (1H, dd, J=2.0Hz and 7.5Hz), 8.21 (1H, t, J=7.5Hz), 8.30 (1H, dd, J=2.0Hz and 7.5Hz), 8.50 (1H, s) Preparation 22 A mixture of 6-hydroxymethyl-2-pyridinecarboxamide (80 g) and acetic anhydride (198.8 ml) in tetrahydrofuran (800 ml) was heated under reflux for 24 hours. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 6-acetoxymethyl-2-pyridinecarboxamide (93.34 g). mp : 92-93°C IR (Nujol) : 3380, 3180, 1730, 1680, 1590 cm-1 NMR (DMSO-άθ, δ) : 2.16 (3H, s), 5.22 (2H, s), 7.61 (1H, dd, J=2.6Hz and 6.3Hz), 7.72 (1H, s), 7.94-8.07 (3H, m) Preparation 23 Phosphorus oxychloride (86.9 ml) was dropwise added to a mixture of 6-acetoxymethyl-2-pyridinecarboxamide (93.0 g) and Ν,Ν-dimethylformamide (74.2 ml) in ethyl acetate (930 ml) under ice-cooling with stirring and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was added to a water and adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 6-acetoxymethyl-2-cyanopyridine (84.0 g) as an oil.

IR (Film) : 2230, 1735, 1670, 1585 cm-1 NMR (DMSO-dg, δ) : 2.15 (3H, s), 5.20 (2H, s), 7.77 (1H, dd, J=0.7Hz and 7.8Hz), 7.99 (1H, dd, J=0,?Hz and 7.8Hz), 8.10 (IH, t, J=7.8Hz) Preparation 24 The following compound was obtained according to a similar manner to that of Preparation 5. 2-Acetyl-6-hydroxymethylpyridine IR (Film) : 1690, 1590 cm1 NMR (CDC13, δ) : 2.74 (3H, s), 3.77 (IH, t, J=4.8Hz), 4.84 (2H, d, J=4.8Hz), 7.45 (IH, d, J=7.6Hz), 7.85 7.96 (IH, d, J=7.6Hz) (IH, t, J=7.6Hz), Preparation 25 Phosphorus oxychloride (7.8 ml) was dropwise added to a mixture of 2-acetyl-6-hydroxymethylpyridine (10.0 g) and Ν,Ν-dimethylformamide (15.4 ml) in ethyl acetate (100 ml) under ice-cooling with stirring and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was added to water and adjusted to pH 7.5 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 2-acetyl-6-chloromethylpyridine (10.85 g) as an oil.

IR (Film) : 1700, 1670, 1585 cm1 NMR (CDC13, δ) : 2.72 (3H, s), 4.73 (2H, s), 7.68 (IH, d, J=7.7Hz), 7.87 (IH, t, J=7.7Hz), 7.98 (IH, d, J=7.7Hz) Preparation 26 A mixture of 2-acetyl-6-chloromethylpyridine (10.8 g) and potassium cyanide (4.1 g) in Ν,Ν-dimethylformamide (108 ml) was stirred under ice-cooling for 1 hour and then the mixture was stirred at ambient temperature for 18 hours.

To the mixture was added to water and extracted with ethyl acetate. The extract layer was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel, eluting with a chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-acetyl-6-cyanomethylpyridine (3.0 g). mp : 57°C IR (Nujol) : 2240, 1690, 1580 cm”1 NMR (DMSO-dg, δ) : 2.66 (3H, s), 4.36 (2H, s), 7.70 (IH, d, J=7.7Hz), 7.92 (IH, d, J=7.7Hz), 8.05 (IH, t, J=7.7Hz) Preparation 27 Phosphorus oxychloride (8.5 ml) was added slowly to a solution of 4-acetyl-2-thiazolecarboxamide (10.0 g) in Ν,Ν-dimethylformamide (500 ml) at 0-5°C with cooling on an ice-water bath. The mixture was stirred at 0-5°C with cooling on an ice-water bath for 4 hours and then was poured into ice water (400 ml). The solution was extracted with ethyl acetate (750 ml x 2). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from water to afford 4-acetyl-2-cyanothiazole (6.7 g). mp : 9 3 °C IR (Nujol) : 3050, 2230, 1680 cm”1 NMR (DMSO-dg, δ) : 2.62 (3H, s), 8.92 (IH, s) Preparation 28 The following compound was obtained according to a similar manner to that of Example 17. 4-(6-Acetylaminomethylpyridin-2-yl)-2-aminothiazole mp : 179-180°C IR (Nujol) : 3380, 3260, 3110, 1655, 1620 cm_i NMR (DMSO-dg, δ) : 1.93 (3H, s), 4.36 (2H, d, J=5.9Hz), 7.11 (2H, s), 7.13 (1H, d, J=7.0Hz), 7.26 (1H, s), 7.68 (1H, d, J=7.0Hz), 7.76 (1H, t, J=7.0Hz), 8.45 (1H, t, J=5.9Hz) Preparation 29 The following compound was obtained according to a similar manner to that of Example 2. 4-(6-Acetylaminomethylpyridin-2-yl)-2-aminothiazole hydrochloride mp : 258°C IR (Nujol) : 3370, 3280, 3220, 1655, 1615, 1590 cm”1 NMR (DMSO-dg, δ) : 2.01 (3H, s), 4.47 (2H, d, J=5.6Hz), 7.33-7.42 (1H, m), 7.68 (1H, s), 7.90-7.99 (2H, m), 8.63 (1H, t, J=5.6Hz) Anal. Calcd. for ^H^^OS’HCVI^O : C 43.64, H 4.99, N 18.50, Cl 11.71, H2O 5.95 Found : C 43.45, H 4.86, N 18.37, Cl 11.78, H2O 5.96 Preparation 30 Benzoyl chloride (15.7 ml) was dropped to a refluxing solution of ammonium thiocyanate (11.3 g) in acetone (640 ml) and the mixture was refluxed for 20 minutes. 4-(6-Acetylaminomethylpyridin-2-yl)-2-aminothiazole (32.0 g) was added portionwise to the refluxing mixture. After the mixture was refluxed for 3 hours, the solvent was evaporated in vacuo and the residue was mixed with ethyl acetate, tetrahydrofuran and water. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and resulting precipitate was collected by filtration to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(3benzoylthioureido)thiazole (15.11 g). mp : 222°C (dec.) IR (Nujol) : 3300, 1670, 1640 cm1 NMR (DMSO-dg, δ) : 1.95 (3H, s), 4.42 (2H, d, J=5.9Hz), 7.19-7.33 (IH, m), 7.49-7.80 (3H, m), 8.82-8.06 (5H, m), 8.50 (IH, t, J=5.9Hz), 12.16 (IH, s), 14.29 (IH, s) Preparation 31 A solution of sodium hydroxide (0.8 g) in water (8 ml) was added to a suspension of 4-(6-acetylaminomethylpyridin-2-yl)-2-(3-benzoylthioureido)thiazole (8.0 g) in methanol (80 ml) and the mixture was stirred at 50-60°C for 1 hour. Following evaporation in vacuo, the residue was mixed with water and the mixture was adjusted to pH 7.5 with 6N-hydrochloric acid. The mixture was extracted with the mixture of tetrahydrofuran and ethyl acetate and extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin-2-yl)-2-thioureidothiazole (5.44 g). mp : 212-213°C IR (Nujol) : 3290, 3190, 1640, 1610 cm-1 NMR (DMSO-dg, + D2O, δ) : 1.94 (3H, s), 4.41 (2H, s), 7.21-7.30 (IH, m), 7.75-7.92 (3H, m) Preparation 32 A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2thioureidothiazole (5.3 g) and methyl iodide (1.2 ml) in a solution of methanol (53 ml) and tetrahydrofuran (25 ml) was heated under reflux for 4.5 hours. The solvent was removed by concentration in vacuo and resulting residue was triturated with ethyl acetate to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)(methylthio)methyleneamino]thiazole hydriodide. mp : 195-197°C (dec.) IR (Nujol) : 3380, 3280, 3190, 1600 (br) cm1 NMR (DMSO-dg, + D2O, δ) : 1.98 (3H, s), 2.56 (3H, s), 4,55 (2H, s), 7.44-7.55 (IH, m) , 7.99-7.09 (IH, m), 7.18-8.24 (2H, m) Preparation 33 The following compound was obtained according to a similar manner to that of Preparation 18. 6-Acetyl-2-pyridinecarbaldehyde 10 mp : 68-69°C IR (Nujol) : 1700 cm-1 NMR (DMSO-dg, δ) : 2.73 (3H, s), 8.12-8.34 (3H, m), .06 (IH, s) Preparation 34 A mixture of 6-acetyl-2-pyridinecarbaldehyde (0.5 g) and cyanomethylenetriphenylphosphorane (1.5 g) in tetrahydrofuran (5 ml) was stirred for 6 hours and the mixture was evaporated in vacuo. The residue was separated and purified by column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (4:1, V/V). The eluted fast fractions containing the desired product were collected and evaporated in vacuo to give 2-acetyl-6-[2-(Έ)-cyanovinyl)pyridine (0.18 g). mp : 117°C IR (Nujol) : 2210, 1690, 1575 cm'1 NMR (DMSO-dg, δ) : 2.68 (3H, s), 6.90 (IH, d, J=16.3Hz), 7.83 (IH, d, J=16.3Hz), 7.87 (IH, dd, J=l.lHz and 7.6Hz), 7.97 (IH, dd, J=l.lHz and 7.6Hz), 8.11 (IH, t, J=7.6Hz) The eluted another fractions containing the desired product were collected and evaporated in vacuo to give 2-acetyl-6-[2-(Z)-cyanovinyl]pyridine (0.26 g). mp : 108-109°C IR (Nujol) : 2210, 1690, 1575 cm x NMR (DMSO-dg, δ) : 2.74 (3H, s), 6.16 (1H, d, J=11.7Hz), 7.57 (1H, d, J=11.7Hz), 7.85 (1H, dd, J=1.2Hz and 7.7Hz), 7.99 (1H, dd, J=1.2Hz and 7.7Hz), 8.14 (1H, t, J=7.7Hz) Preparation 35 % Palladium on carbon (0.8 g) was added to a mixture of 2-acetyl-6-[2-(E,Z)-cyanovinyl]pyridine (0.5 g) in methanol (15 ml) and the mixture was subjected to catalytic reduction under atmospheric pressure at ambient temperature for 7 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give 2-(2-cyanoethyl)-6-(1-hydroxyethyl)pyridine (0.47 g) as an oil.

IR (Film) : 3380 (br), 2250, 1595, 1580 cm1 NMR (DMSO-dg, δ) : 1.37 (3H, d, J=6.7Hz), 2.87 (2H, t, J=6.8Hz), 3.02 (2H, t, J=6.8Hz), 4.70-4.75 (1H, m), 5.34-5.38 (1H, m), 7.18 (1H, d, J=7.6Hz), 7.39 (1H, d, J=7.6Hz), 7.74 (1H, t, J=7.6Hz) Preparation 36 The following compound was obtained according to a similar manner to that of Preparation 18. 2-Acetyl-6-(2-cyanoethyl)pyridine IR (Film) : 2250, 1695, 1590 cm1 NMR (DMSO-dg, δ) : 2.66 (3H, s), 2.98 (2H, t, 30 J=6.7Hz) , 3.18 (2H, t, J=6.7Hz), 7.63 (1H, d, J=7.6Hz) , 7.84 (1H, d, J=7.6Hz), 7.97 (1H, t, J=7.6Hz) Preparation 37 The following compound was obtained according to a similar manner to that of Preparation 11.

Methyl 6-bromoacetyl-2-pyridinecarboxylate IR (Film) : 1715 cm1 NMR (DMSO-dg, δ) : 3.95 (3H, s), 5.15 (2H, s), 8.13-8.35 (3H, m) Preparation 38 wt % Hydrogen peroxide (80.3 ml) was added dropwise to a solution of 2-(2-acetylaminoethyl)pyridine (64.5 g) in acetic acid (65 ml) at 70-75°C and the mixture was stirred at the same temperature for 8 hours. After the mixture was ice-cooled and the mixture was added to a mixture of sodium sulfite (56.9 g) in ice water (200 ml).

The solvent was removed by concentration in vacuo and the residue was extracted with a tetrahydrofuran. The extract solution was dried over magnesium sulfate and evaporated to give 2-(2-acetylaminoethyl)pyridine N-oxide (70.82 g).

IR (Nujol) : 1640 cm 1 NMR (DMSO-dg, δ) : 1.76 (3H, s), 2.93 (2H, t, J=6.7Hz), 3.34-4.34 (2H, m), 7.25-7.40 (3H, m), 7.99 (IH, m), 8.24-8.32 (IH, m) Preparation 39 A mixture of 2-(2-acetylaminoethyl)pyridine N-oxide (70.8 g) and dimethyl sulfate (41 ml) was stirred at ambient temperature for 1.5 hours. To the mixture was added dimethylsulfoxide (420 ml) and potassium cyanide (25.6 g) and the mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was added water and extracted with chloroform. The extract layer was dried over magnesium sulfate and evaporated in vacuo to give 2-(2-acetylaminoethyl)-6-cyanopyridine (74.3 g) · IR (Nujol) : 3270, 2230, 1660 cm-1 NMR (DMSO-dg, δ) : 1.76 (3H, s), 2.92 (2H, t, J-7.0HZ), 3.35-3.50 (2H, m), 7.61 (1H, dd, J=1.3Hz and 7.6Hz), 7.86-8.02 (3H, m) Preparation 40 The following compound was obtained according to a similar manner to that of Preparation 5. 2-Acetyl-6-(2-acetylaminoethyl)pyridine 10 mp : 74-76°C IR (Nujol) : 3320, 1690, 1630, 1580 cm1 NMR (DMSO-dg, δ) : 1.78 (3H, s), 2.64 (3H, s), 2.96 (2H, t, J=7.lHz), 3.42-3.52 (2H, m) , 7.52 (1H, dd, J=l.lHz and 7.6Hz), 7.79 (1H, dd, J=l.lHz, 7.6Hz), 7.87-7.92 (1H, m), 7.91 (1H, t, J=7.6Hz) Preparation 41 The following compound was obtained according to a 20 similar manner to that of Preparation 44. 2-(2-Acetylaminoethyl)-6-bromoacetylpyridine mp : 101-103°C IR (Nujol) : 3280, 1708, 1630 cm1 NMR (DMSO-dg, δ) : 1.78 (3H, s), 2.97 (2H, t, J=7.0Hz), 3.44-3.53 (2H, m), 5.07 (2H, s), 7.58 (1H, dd, J=1.3Hz and 7.5Hz), 7.84-8.02 (3H, m) Preparation 42 The following compound was obtained according to a similar manner to that of Example 62. 2-Acetylamino-6-cyanopyridine 35 mp : 191-193°C (dec.) IR (Nujol) : 3230, 2240, 1665, 1580 cm L NMR (DMSO-dg, δ) : 2.12 (3H, s), 7.72 (IH, dd, J=0.7Hz and 7.5Hz), 8.01 (IH, t, J=7.5Hz), 8.37 (IH, dd, J=0.7Hz and 7.5Hz), 10.95 (IH, s) Preparation 43 The following compound was obtained according to a similar manner to that of Preparation 5. 2-Acetyl-6-acetylaminopyridine mp : 134-135°C IR (Nujol) : 3350, 1690 cm-1 NMR (DMSO-dg, δ) : 2.16 (3H, s), 2.62 (3H, s), 3.65 (IH, d, J=7.9Hz), 7.96 (IH, t, J=7.9Hz), 8.30 (IH, d, J=7.9Hz), 10.62 (IH, s) Preparation 44 Bromine (1.9 ml) was added dropwise to a mixture of 2-acetyl-6-acetylaminopyridine (6.6 g) and 30 wt % hydrogenbromide-acetic acid solution (7.4 ml) in acetic acid (66 ml) at ambient temperature under stirring and the mixture was stirred at 50°C for 1.5 hours. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 2-acetylamino-6-bromoacetylpyridine (8.57 g). mp : 118-121°C IR (Nujol) : 3300, 1715, 1665 cm-1 NMR (DMSO-dg, δ) : 2.16 (3H, s), 4.99 (2H, s), 7.72 (IH, d, J=7.5Hz), 8.00 (IH, t, J=7.5Hz), 8.33 (IH, d, J=7.5Hz), 10.68 (IH, s) Preparation 45 A solution of 4-(acetylaminomethyl)pyridine N-oxide (17.5 g), trimethylsilanecarbonitrile (53 ml) and triethylamine (43 ml) in acetonitrile (180 ml) was refluxed for 7 hours with stirring. After evaporation of the solvent, the residue was diluted with water and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (430 g) by eluting with a mixture of ethyl acetate and methanol (50:1) followed by recrystallization with a mixture of ethyl acetate and diisopropyl ether to give 4-(acetylaminomethyl)-2-pyridinecarbonitrile (8.66 g) mp : 116-117°C IR (Nujol) : 3370, 3060, 2240, 1640 cm-1 NMR (DMSO-dg, δ ) : 1.94 (3H, s), 4.35 (2H, d, 15 J=6.0Hz), 7.59 (IH, dd, J=0.8 and 5.1Hz), 7.90 (IH, d, J=0.8Hz), 8.52 (IH, t, J=6.0Hz), 8.68 (IH, d, J=5.lHz) Preparation 46 The following compound was obtained according to a similar manner to that of Preparation 5. 2-Acetyl-4-(acetylaminomethyl)pyridine mp : 95-96°C IR (Nujol) : 3290, 3075, 1690, 1645 cm-1 NMR (DMSO-dg, 6) : 1.92 (3H, s), 2.63 (3H, s), 4.36 (2H, d, J=6.0Hz), 7.52 (IH, dd, J=0.9Hz and 4.9Hz), 7.84 (IH, d, J=0.9Hz), 8.54 (IH, t, J=6.0Hz), 8.65 (IH, d, J=4.9Hz) Preparation 47 The following compound was obtained according to a similar manner to that of Preparation 6. 4-( Acetylaminomethyl)-2-bromoacetylpyridine mp : 84-86°C IR (Nujol) : 3390, 1710, 1645 cm1 NMR (CDC13, δ) : 2.04 (3H, s), 4.46 (2H, s), 7.53 (IH, dd, J=0.8Hz and 5.1Hz), 7.92 (IH, d, J=0.8Hz), 8.49 (IH, d, J=5.1Hz) Preparation 48 A solution of ferrous sulfate heptahydrate (496 g) in water (1080 ml) and tert-butylhydroperoxide (173 ml) were simultaneously added to a solution of 4-pyridinecarbonitrile (30 g), acetaldehyde (97.6 ml) and sulfuric acid (15.4 ml) in water (90 ml) at 0°C with stirring. After stirring at the same temperature for one hour, the resulting precipitate was collected by filtration and washed with water to give 2-acetyl-4-pyridinecarbonitrile (22.5 g). mp : 95-96°C IR (Nujol) : 2240, 1690 cm1 NMR (DMSO-dg, δ) : 2.67 (3H, s), 8.15 (IH, dd, J=1.3Hz and 4.6Hz), 8.30 (IH, d, J=1.3Hz), 8.99 (IH, d, J=4.6Hz) Preparation 49 The following compound was obtained according to a similar manner to that of Preparation 11. 2-Bromoacetyl-4-pyridinecarbonitrile hydrobromide mp : 151-152°C IR (Nujol) : 1720 cm1 NMR (DMSO-dg, δ) : 4.97 (2H, s), 8.17 (IH, dd, J=1.0Hz and 4.6Hz), 8.31 (IH, d, J=1.0Hz), 8.99 (IH, d, J=4.6Hz) Preparation 50 % Hydrogen peroxide (130 ml) was added to ethyl pyruvate (216 g) at -5 to 5°C with stirring. This solution was then added to a mixture of 4-acetylpyridine (15.0 g), concentrated sulfuric acid (12.4 g), ferrous sulfate heptahydrate (345 g), dichloromethane (1.5 t) and water (100 ml) at the same temperature with stirring.

After further stirring for 30 minutes, the resulting organic layer was separated. The solution was washed with aqueous sodium sulfite and then water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography by eluting with a mixture of ethyl acetate and toluene (1:20) to give ethyl 4-acetyl-2-pyridinecarboxylate (5.79 g). mp : 43-44°C IR (Nujol) : 1715, 1690 cm1 NMR (DMSO-dg, δ) : 1.36 (3H, t, J=7.1Hz), 4.40 (2H, q, J=7.1Hz), 8.08 (1H, dd, J=1.7Hz and 4.9Hz), 8.35 (1H, d, J=1.7Hz), 8.95 (1H, d, J=4.9Hz) Preparation 51 The following compound was obtained according to a similar manner to that of Preparation 6.

Ethyl 4-bromoacetyl-2-pyridinecarboxylate hydrobromide mp : 169-170°C IR (Nujol) : 1745, 1715 cm 1 NMR (CD3OD, δ) : 1.50 (3H, t, J=7.1Hz), 4.61 (2H, q, J=7.1Hz), 8.39 (1H, d, J=1.8Hz and 5.9Hz), 8.63 (1H, d, J=1.8Hz), 8.98 (1H, d, J=5.9Hz) Preparation 52 The following compound was prepared according to a similar manner to that of Preparation 48.

Methyl 6-acetyl-4-chloro-2-pyridinecarboxylate mp : 98-99°C IR (Nujol) : 1725, 1710 cm1 NMR (DMSO-dg, δ) : 2.67 (3H, s), 3.96 (3H, s), 8.15 (1H, d, J=2.0Hz), 8.29 (1H, d, J=2Hz) Preparation 53 A solution of methyl 6-acetyl-4-chloro-2-pyridinecarboxylate (6.55 g) and surfuryl chloride (2.73 ml) in acetic acid (33 ml) was stirred at ambient temperature for 14 hours and further at 50°C for three hours. The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and washed with water to give methyl 4-chloro-6-chloroacetyl-2-pyridinecarboxylate (6.75 g). mp : 115-118°C IR (Nujol) : 1725 cm1 NMR (DMSO-dg, δ) : 3.95 (3H, s), 5.29 (2H, s), 8.27 (1H, d, J=2.0Hz), 8.35 (1H, d, J=2.0Hz) Preparation 54 A mixture of 2-acetylaminomethylpyridine N-oxide (1.00 g) and dimethyl sulfate (0.63 ml) was stirred for three hours. Dimethyl sulfoxide (6 ml) and potassium cyanide (392 mg) were added to the mixture and the solution was stirred for two hours at ambient temperature. Additional potassium cyanide (392 mg) was added to the mixture and which was further stirred for two hours.

After the solvent was removed by concentration, the residue was mixed with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g) by eluting with a mixture of ethyl acetate and methanol (20:1) to give 6-acetylaminomethyl-2-pyridinecarbonitrile (0.16 g).

IR (Nujol) : 3260, 2230, 1650 cm1 Preparation 55 The following compound was obtained according to a similar manner to that of Preparation 48. 2-Acetyl-6-(acetylaminomethyl)pyridine IR (Nujol) : 3300, 1690, 1650 cm1 Preparation 56 The following compound was obtained according to a 10 similar manner to that of Preparation 48. 4-Acetyl-2-carbamoylpyridine mp : 182 to 183°C IR (Nujol) : 3440, 3320, 1690 cm1 NMR (DMSO-dg, δ) : 2.69 (3H, s), 7.82 (IH, s), 8.01 (IH, dd, J=1.7Hz and 15.0Hz), 8.25 (IH, s), 8.40 (IH, d, J=1.7Hz), 8.86 (IH, d, J=5.0Hz) Preparation 57 The following compound was obtained according to a similar manner to that of Preparation 6. 4-Bromoacetyl-2-carbamoylpyridine hydrobromide mp : >300°C IR (Nujol) : 3280, 3240, 3150, 1710, 1690 cm1 NMR (CD3OD, δ) : 4.93 (2H, s), 8.38 (IH, dd, J=1.7Hz and 5.9Hz), 8.78 (IH, d, J=1.7Hz), 8.96 (IH, d, J=5.9Hz) Preparation 58 Bromine (6.0 g) was added slowly to a solution of -acetyl-3-pyridinecarboxylic acid methyl ester (6.0 g) in dioxane (50 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and then heated at 60-70°C for 5 hours. The resulting precipitate was collected by filtration to afford -bromoacetyl-3-pyridinecarboxylic acid methyl ester hydrobromide (10.0 g).

IR (Nujol) : 3060, 1735, 1705 cm-1 NMR (DMSO-dg, δ) : 3.94 (3H, s), 5.11 (2H, s), 8.73 (IH, t, J=2.1Hz), 9.30 (IH, d, J=2.1Hz), 9.38 (IH, d, J=2.1Hz) Preparation 59 A suspension of 5-acetyl-3-pyridinecarboxylic acid methyl ester (5.0 g) in 28% ammonia solution (30 ml) was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration to afford 3-acetyl-5-carbamoylpyridine (3.38 g). mp : 158-160°C NMR (DMSO-dg, δ) : 2.68 (3H, s), 7.76 (IH, s), 8.36 (IH, s), 8.68 (IH, t, J=2.1Hz), 9.22 (IH, d, J=2.1Hz), 9.23 (IH, d, J=2.lHz) Preparation 60 Phosphorus oxychloride (2.75 g) was added to a solution of 3-acetyl-5-carbamoylpyridine (2.8 g) in Ν,Ν-dimethylformamide (30 ml) with cooling on an ice-water bath. The mixture was stirred with cooling for 1.5 hours.

The solvent was removed under reduced pressure. The residue was dissolved in water (150 ml) and the mixture was extracted with ethyl acetate (100 ml). The extract was dried with magnesium sulfate and then evaporated. The residue was chromatographed on a silica gel column eluting with chloroform to afford 3-acetyl-5-cyanopyridine (1.21 g) · mp : 9 2 ° C IR (Nujol) : 3060, 2250, 1690 cm”1 NMR (DMSO-dg, δ) : 2.67 (3H, s), 8.82 (IH, t, J=2.1Hz), 9.24 (IH, d, J=2.1Hz), 9.32 (IH, d, J=2.1Hz) Example 1 A mixture of 2-(acetylaminometyl)-6-bromoacetylpyridine hydrobromide (3.34 g) and diaminomethylenethiourea (1.01 g) in methanol (50 ml) was 5 refluxed for 10 hours with stirring. The resulting precipitate was collected, dissolved in water (50 ml) and the solution was made basic with agueous potassium carbonate. The separated product was collected and washed with water to give 4-{6-aminomethylpyridin-2-yl)-210 (diaminomethyleneamino)thiazole (0.90 g). mp : 228-229°C IR (Nujol) : 3350, 3150 NMR (DMSO-dg, δ) : 3.85 (2H, s), 6.96 (4H, br s), 7.22-7.44 (3H, m), 7.73-7.83 (3H, m) Example 2 Acetic anhydride was added dropwise to a solution of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.44 g) in pyridine (4.4 ml). After being stirred for two hours at ambient temperature, the mixture was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin-2-yl)-225 (diaminomethyleneamino)thiazole. The residue was converted to the hydrochloride in a usual manner and the salt was recrystallized from a mixture of methanol and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-( diaminomethylene30 amino)thiazole dihydrochloride (0.43 g). mp : 218-219°C IR (Nujol) : 3340, 3160, 1705, 1650 cm1 NMR (DMSO-dg, δ) : 1.96 (3H, s), 4.56 (2H, d, J=6Hz), 7.45 (1H, d, J=7.5Hz), 8.10 (1H, t, J=7.5Hz), 8.24 (1H, d, J=7.5Hz), 8.25 (1H, s). 8.46 (4H, br s), 8.74 (1H, t, J=6Hz) Anal. Calcd. for C12H14N6OS*2HC1’2/3H2° : C 38.41, H 4.66, N 22.39, Cl 18.89, H2O 3.20 found : C 38.14, H 4.56, N 22.25, Cl 19.06, Η2<0 2.65 5 Example 3 A mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole (0.50 g) and dimethyl N-cyanodithioiminocarbonate [(CH^S)2C=N-CN] (0.29 g) in ethanol (10 ml) was refluxed for one hour to give 2-(diaminomethyleneamino)-4-(6-(3-cyano-2-methylisothioureido)methylpyridin-2-yl]thiazole of a crude product. After being concentrated to dry the above product, 40 weight % methanolic methylamine (1.6 ml) and Ν,Ν-dimethylformamide (10 ml) was added and the mixture was stirred at 60°C for 5 hours. The solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and recrystallized from aqueous Ν,Ν-dimethylformamide to give 4-(6-(2-cyano-3-methylguanidino)methylpyridin-2-y1]-2(diaminomethyleneamino)thiazole (0.42 g). mp : 245-246°C IR (Nujol) : 3440, 3400, 3290, 2170, 1630 cm-1 NMR (DMSO-dg, 6) : 2.76 (3H, d, J=4.5Hz), 4.46 (2H, d, J=5.5Hz), 6.93 (4H, s), 7.14-7.26 (2H, m), 7.42 (1H, s), 7.57 (1H, t, J=5.5Hz), 7.79-7.88 (2H, m) Anal. Calcd. for ci3Hi5N9S’ 1/41^0 : C 46.76, H 4.68, N 37.76, H2O 1.34 found : C 46.93, H 4.65, N 37.46, H2O 1.14 Example 4 A mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole (0.64 g), lN-hydrochloric acid (5.15 ml) and potassium cyanate (0.21 g) in water (6.4 ml) was stirred for 19 hours at ambient temperature. The solution was made basic with aqueous potassium carbonate and the resulting precipitate was collected by filtration. The free base was converted to the hydrochloride in a usual manner followed by recrystallization from aqueous methanol to give 2-(diaminomethyleneamino)-4-(6-ureidomethylpyridin-2-yl)thiazole dihydrochloride (0.45 g). mp : 210-211°C IR (Nujol) : 1705, 1650 cm-1 NMR (DMSO-dg, δ) : 4.57 (2H, s), 7.64 (IH, d, J=7.5Hz), 8.26-8.41 (2H, m), 8.51 (10H, s) Anal. Calcd. for C11H13N?OS·2HC1·1/3H2O : C 35.68, H 4.26, N 26.48, Cl 19.15, H2O 1.62 found : C 35.74, H 4.21, N 26.25, Cl 19.46, H2O 1.73 Example 5 A mixture of 2-acetylaminomethyl-5bromoacetylthiazole (6.30 g) and diaminomethylenethiourea [(H2N)2C=NCSNH23 (1.77 g) in acetone (90 ml) was refluxed for 10 hours with stirring. The resulting precipitate was collected by filtration to give 4-(2-acetylaminomethylthiazol-5-yl)-2-(diaminomethyleneamino)thiazole dihydrobromide (2.21 g). mp : 218-219°C IR (Nujol) : 3280, 3200, 3150, 1675, 1655 cm-1 NMR (DMSO-dg, δ) : 1.92 (3H, s), 4.52 (2H, d, J=6Hz), 7.67 (IH, s), 8.25 (IH, s), 8.27 (4H, s), 8.85 (IH, t, J=6Hz), 12.11 (IH, br s) MS (m/e) : 296 Example 6 The following compound was obtained from 4-(2acetylaminomethylthiazol-5-yl)-2-(diaminomethyleneamino)35 thiazole dihydrobromide according to a similar manner to that of Example 10. 4-{2-Aminomethylthiazol-5-yl)-2-(diaminomethyleneamino) thiazole mp : 189-191°C IR (Nujol) : 3430, 3260, 1650, 1630 cm1 NMR (DMSO-dg, δ) : 3.97 (2H, s), 6.93 (4H, s), 7.00 (IH, s), 7.97 (IH, s) Example 7 A mixture of 4-(2-aminomethylthiazol-5-yl)-2(diaminomethyleneamino)thiazole (0.45 g) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N-CN] (0.26 g) in ethanol (10 ml) was refluxed for 5 hours with stirring to give 4-[2-(3-cyano-2-methylisothioureido)methylthiazol15 5-yl]-2-(diaminomethyleneamino)thiazole as a crude product. After cooling to ambient temperature, 40% aqueous methylamine by weight (1.4 ml) was added to the suspension and the mixture was stirred for 12 hours at ambient temperature. The solvent was evaporated in vacuo and the residue was mixed with water (5 ml) and ethyl acetate (5 ml). The resulting precipitate was collected and recrystallized from aqueous Ν,Ν-dimethylformamide to give 4-[2-(2-cyano-3-methylguanidino)methylthiazol-5-yl]2- (diaminomethyleneamino) thiazole (0.3 5 g). mp : 258-259°C IR (Nujol) : 3480, 3360, 3270, 2150 cm1 NMR (DMSO-dg, δ) : 2.74 (3H, d, J=4.5Hz), 4.59 (2H, d, J=6Hz), 6.92 (4H, s), 7.08 (IH, s), 7.32 (IH, q, J=4.5Hz), 7.85 (IH, t, J=6Hz), 8.04 (IH, s) Anal. Calcd. for cj_]_H2.3N9S2 : C 39.39, H 3.91, N 37.59 Found : C 39.30, H 3.95, N 37.40 Example 8 A solution of 4-(2-acetylaminomethylthiazol-5-yl)-2Ί°> (diaminomethyleneamino)thiazole (1.46 g) and concentrated hydrochloric acid (2.18 ml) in ethanol (15 ml) was refluxed for 5 hours with stirring. The solvent was evaporated in vacuo. The residue was made basic to pH 10 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo to give 4-(2-aminomethylthiazol-5-yl)-2-(diaminomethyleneamino) thiazole. ΙΝ-hydrochloric acid (4 ml) and then potassium cyanate (360 mg) was added to the suspension of the above residue in water (10 ml) and the mixture was stirred for two hours at ambient temperature. The reaction mixture was alkalized to pH 10 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo. The obtained free base was converted to the dihydrochloride in an usual manner, and which was recrystallized from a mixture of methanol, water and tetrahydrofuran to give 2-(diamino20 methyleneamino)-4-(2-ureidomethylthiazol-5-yl)thiazole dihydrochloride (0.65 g). mp : 184-185°C IR (Nujol) : 3250, 3100, 1660 cm1 NMR (DMSO-dg, δ) : 4.46 (2H, s), 6.21 (4H, br s), 7.62 (1H, s), 8.27 (1H, s), 8.37 (4H, s), 12.85 (1H, br s) Example 9 Bromine (2.2 g) was added slowly to a solution of 4-acetyl-2-acetylaminomethylthiazole (2.2 g) in acetic acid (20 ml) and water (20 ml), and the mixture was heated at 70°C for 4 hours. The solvent was removed under reduced pressure to give crude product of 2-acetylaminomethyl-4-bromoacetylthiazole. The above residue was dissolved in ethanol (50 ml).

Diaminomethylenethiourea (1.3 g) was added to the solution and the mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and then the solution was alkalized with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. The filtrate was extracted by ethyl acetate and then the solvent was removed under reduced pressure. The residue and the precipitate were chromatographed on an alumina column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino) thiazole (430 mg). mp : 255-256°C IR (Nujol) : 3250, 1640 cm 1 NMR (DMSO-dg, δ) : 1.91 (3H, s), 4.54 (2H, d, J=5.9Hz), 6.88 (4H, s), 7.02 (IH, s), 7.79 (IH, s), 8.77 (IH, t, J=5.9Hz) Anal. Calcd. for C1QH12NgOS2·4/5H 2° 20 C 38.65, H 4.41, N 27.04 Found : C 38.51, H 4.31, N 27.00 Example 10 Concentrated hydrochloric acid (72.4 ml) was added 25 slowly to a suspension of 4-(2-acetylaminomethylthiazol4-yl)-2-(diaminomethyleneamino)thiazole (6.58 g) in ethanol (280 ml). The mixture was refluxed for 2 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 4-(2-aminomethylthiazol-4-yl)-2(diaminomethyleneamino)thiazole dihydrochloride (6.98 g). mp : >300°C IR (Nujol) : 3300, 1680, 1600 cm 1 NMR (DMSO-dg, 6) : 4.47 (2H, s), 7.59 (IH, s), 8.41 (4H, s), 8.45 (IH, s), 8.76 (3H, s), 12.82 (1H, s) Anal. Calcd. for CgH10NgS2‘2HCl-9/10H2O C 27.98, H 4.05, N 24.47, Cl 20.64, H20 4.72 Found: C 27.69, H 3.87, N 24.13, Cl 20.85, HjO 4.38 Example 11 A solution of 4-(2-aminomethylthiazol-4-yl)-2(diaminomethyleneamino)thiazole (1.0 g) and potassium cyanate (0.5 g) in water (50 ml) was stirred for 3.5 hours at room temperature. The resulting precipitate was collected by filtration. The precipitate was suspended in water (30 ml) and then a saturated agueous potassium carbonate solution (20 ml) was added. The mixture was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration.

Recrystallization from a mixture of methanol and water afforded 2-(diaminomethyleneamino)-4-(2-ureidomethylthiazol-4-yl)thiazole (0.35 g). mp : 261-262 ° C (dec.) -1 IR (Nujol) : 3450, 3350, 1660, 1630 cm NMR (DMSO-dg, δ) : 4.46 (2H, d, J=6. 1Hz), 5.77 (2H, s), 6.80 (1H, t, J=6.1Hz), 6.88 (4H, s), 7. 01 (1H, s). 7.76 (1H, s) Anal. Calcd. for C9HnN7OS2 : C 36.35, H 3.73, N 32.97 Found : C 36.52, H 3.72, N 33.36 Example 12 Methanesulfonic acid (2.16 g) was added to a 30 suspension of 2-(diaminomethyleneamino)-4-(2ureidomethylthiazol-4-yl)thiazole (3.19 g) in methanol (95 ml). The mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration. Recrystallization from a mixture of acetonitrile and water afforded 2-(diaminomethyleneamino)82 4-(2-ureidomethylthiazol-4-yl)thiazole methanesulfonate (3.2 g). mp : 257-259°C (dec.) IR (Nujol) : 3490, 3320, 1680, 1610 cm-1 NMR (DMSO-dg, δ) : 2.48 (3H, s), 4.49 (2H, d, J=6.0Hz), 5.82 (2H, s), 6.89 (IH, t, J=6.0Hz), 7.56 (IH, s), 8.20 (IH, s), 8.34 (4H, s), 12.03 (IH, s) Example 13 Triethylamine (0.7 g) was added to a suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (1.0 g) in methanol (20 ml). To the mixture was added methylisocyanate (0.21 g). The mixture was stirred at room temperature for 1.5 hours. The solvent was removed under the reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1).

Recrystallization from a mixture of water and methanol afforded 2-(diaminomethyleneamino)-4-[2-(3methylureido)methylthiazol-4-yl]thiazole (0.5 g). mp : 229-230°C (dec.) IR (Nujol) ; 3425, 3330, 1630, 1610 cm-1 NMR (DMSO-dg, δ) : 2.59 (3H, d, J=4.6Hz), 4.48 (2H, d, J=6.1Hz), 6.08 (IH, g, J=4.6Hz), 6.80 (IH, t, J=6.1Hz), 6.90 (4H, s), 7.01 (IH, s), 7.75 (IH, s) Anal. Calcd. for ciqhi3N7OS2 : C 38.57, H 4.21, N 31.49 Found : C 38.37, H 4.04, N 31.17 Example 14 A solution of 4-acetylthiazole-2-carboxylic acid ethyl ester (1.5 g) and bromine (1.4 g) in methanol (50 ml) was stirred for 8 hours at room temperature. The solvent was removed under reduced pressure to give 4-bromoacetylthiazole-2-carboxylic acid ethyl ester.

A suspension of the above residue and diaminomethylenethiourea (800 mg) in ethanol (50 ml) was 5 refluxed for 4 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-[2-(diaminomethyleneamino)thiazol-4-yl]thiazole-2carboxylic acid ethyl ester hydrobromide (800 mg). mp : 227°C (dec.) IR (Nujol) : 3400, 3140, 1725, 1680, 1630, 1605 cm1 NMR (DMSO-dg, δ) : 1.36 (3H, t, J=7.lHz), 4.42 (2H, q, J=7.lHz), 7.77 (1H, s), 8.25 (4H, s), 8.75 (1H, s), 12.04 (1H, s) Anal. Calcd. for C^qH^^N^O2S2’HBr : C 31.75, H 3.20, Ν 18.51, Br 21.12 Found : C 31.33, H 3.15, N 18.55, Br 21.47 Example 15 Bromine (1.3 g) was added slowly to a suspension of 4-acetylthiazole-2-carboxamide (1.3 g) in methanol (50 ml). The mixture was stirred for 3.5 hours at room temperature. The solvent was removed under reduced pressure to give 4-bromoacetylthiazole-2-carboxamide. The above residue and diaminomethylenethiourea (900 mg) were suspended in ethanol (50 ml) and the mixture was refluxed for 24 hours. The resulting precipitate was collected by filtration and suspended in water (50 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from methanol afforded 4-[2-(diaminomethyleneamino)thiazol-4yl]thiazole-2-carboxamide (1.05 g). mp : 265-266°C (dec.) IR (Nujol) : 3460, 3330, 1670, 1630 cm1 NMR (DMSO-dg, δ) : 6.92 (4H, s), 7.19 (1H, s), 7.93 (1H, s), 8.16 (1H, s), 8.17 (1H, s) Example 16 A suspension of 4-[2-(diaminomethyleneamino)thiazol4-yl]thiazole-2-carboxamide (1.0 g) in 4N-hydrogenchloride/dioxane (1.0 ml) and methanol (10 ml) was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration.

Recrystallization from water afforded 4-(2-(diaminomethyleneamino)thiazol-4-yl) thiazole-2carboxamide hydrochloride (850 mg). mp : >300°C IR (Nujol) : 3350, 3150, 1670, 1600 cm-1 NMR (DMSO-dg, δ) : 7.69 (1H, s), 7.99 (1H, s), 8.24 (1H, s), 8.38 (4H, s), 8.62 (1H, s), 12.74 (1H, br) Anal. Calcd. for CgHgNgOS2-HCl-I^O : C 29.77, H 3.43, N 26.04, Cl 10.98, H2O 5.58 Found : C 29.68, H 3.40, N 25.96, Cl 11.07, H2O 6.20 Example 17 A mixture of 2-{acetylaminomethyl)-6bromoacetylpyridine (50.0 g) and diaminomethylenethiourea (15.3 g) in ethanol (400 ml) was stirred at 40 to 50°C for hours. The solvent was removed by concentration in vacuo. To the residue was added a mixture of water, ethyl acetate and tetrahydrofuran, and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (85:15, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole (18.73 g). mp : 198-200°C IR (Nujol) : 1655, 1590, 1545 cm”1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 4.35 (2H, d, J=6Hz), 6.90 (4H, br s), 7.14 (IH, t, J=4Hz), 7.39 (IH, s), 7.76 (IH, d, J=4Hz), 8.39 (IH, t, J=6Hz) Example 18 4N-Dioxanic hydrogen chloride (48.0 ml) was added dropwise to a solution of 4-(6-acetylaminomethylpyridin2-yl)-2-(diaminomethyleneamino)thiazole (18.6 g) in methanol (50 ml) at ambient temperature for 5 minutes.

After the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a diisopropyl ether and the isolated precipitate was collected by filtration. The precipitate was recrystallized from a mixture of methanol and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole dihydrochloride (16.29 g).

IR (Nujol) : 3340, 3160, 1705, 1650 cm”1 Example 19 The following compound was obtained according to a similar manner to that of Example 17. 2-(Diaminomethyleneamino)-4-(6-propionylaminomethyl30 pyridin-2-yl)thiazole mp : 216-217°C IR (Nujol) : 3290, 1642, 1602, 1590, 1530 cm”1 NMR (DMSO-dg, δ) : 1.06 (3H, t, J=7.6Hz), 2.22 (2H, g, J=7.6Hz), 4.38 (2H, d, J=5.9Hz), 6.94 (4H, s), 7.11-7.19 (IH, m), 7.41 (IH, s), - 86 Anal. Calcd. for C1OH1CN,OS 13 16 6 C 51.30, H C 50.99, H 74-7.84 (2H, m), 8.38 (1H, t, J=5.9Hz) .30, N 27.61 5.19, N 27.32 Found Example 20 Acetoxvacetvl chloride (0.7 g) was added to a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole trihydrochloride (1.5 g) and triethylamine 10 (2.6 ml) in dichloromethane (30 ml) under ice-cooling and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium 15 carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was separated and purified by column chromatograpy on silica gel, and eluted with a mixture of chloroform and methanol (9:1, V/V). The eluted fast 20 fractions containing the desired were collected and evaporated in vacuo to give 4-(6-acetoxyacetylaminomethylpyridin-2-yl)-2-[(acetoxyacetylamino)(amino)methyleneamino]thiazole (0.3 g). mp : 148-151°C IR (Nujol) : 3380, 1740, 1660, 1630, 1570, 1530 cm'1 NMR (DMSO-dg, δ) : 2.12 (6H, s), 4.45 (2H, d, J=5.9Hz), 4.59 (2H, s), 4.70 (2H, s), 7.21 (IH, d, J=7.3Hz), 7.73 (IH, s), 7.80-7.94 (2H, m), 8.65 (IH, t, J=5.9Hz) The eluted another fractions containing the desired product were collected and evaporated in vacuo.

The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-(635 acetoxyacetylaminomethylpyridin-2-yl)-2-(diaminomethylene87 amino)thiazole (0.3 g). mp : 231°C (dec.) IR (Nujol) : 3390, 1743, 1683, 1660, 1610, 1550 cm1 NMR (DMSO-dg, δ) : 2.12 (3H, s), 4.43 (2H, d, J=5.9Hz), 4.58 (2H, s), 6.93 (4H, s), 7.10-7.20 (IH, m), 7.42 (IH, s), 7.75-7.85 (2H, m), 8.64 (IH, t, J=5.9Hz) Anal. Calcd. for C-.H. 16 6 3 C 48.27, H 4.63, N 24.12 10 Found : C 48.24, H 4.48, N 24.25 Example 21 A mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole trihydrochloride (1.5 g), triethylamine (1.8 ml), (furfurylthio)acetic acid (0.8 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.0 g) in Ν,Ν-dimethylformamide (15 ml) was stirred at ambient temperature for 18 hours. The mixture was added to a mixture of ethyl acetate and water and the separated organic layer was dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-[6(furfurylthio)acetylaminomethylpyridin-2-yl)thiazole (0.73 9) · mp : 182°C IR (Nujol) : 3390, 3300, 1660, 1600 cm1 NMR (DMSO-dg, δ) : 3.24 (2H, s), 3.90 (2H, s), 4.41 (2H, d, J=5.7Hz), 6.28 (IH, d, J=3.1Hz), 6.38 (IH, dd, J=1.9Hz, 3.1Hz), 6.93 (4H, s), 7.17-7.23 (IH, m), 7.43 (IH, s), 7.57-7.58 (IH, m), 7.79-7.85 (2H, m), 8.63 (IH, t, J=5.7Hz) Anal. Calcd. for C^-IL oNr0_Sn : 18 6 2 2 C 50.73, H 4.51, N 20.88 Found : C 50.55, H 4.60, N 20.40 Example 22 Methyl isocyanate (0.24 ml) was added to a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.2 g) and triethylamine (1.4 ml) in a solution of tetrahydrofuran (18 ml) and methanol (6 ml) and the mixture was stirred at ambient temperature for 1 hour. To the mixture was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was dried over magnesium sulfate and evaporated to give 2-(diaminomethyleneamino)-4-[6-(3methylureido)methylpyridin-2-yl]thiazole (0.92 g). mp : 205-206°C IR (Nujol) : 3320, 1620, 1590 cm1 NMR (DMSO-dg, δ) : 2.59 (3H, d, J=4.7Hz), 4.32 (2H, d, J=5.8Hz), 6.07 (1H, q, J=4.7Hz), 6.51 (1H, t, J=5.7Hz), 6.98 (4H, s), 7.14-7.21 (1H, m), 7.46 (1H, s), 7.77-7.79 (2H, m) Example 23 The following compound was obtained according to a similar manner to that of Example 18. 2-(Diaminomethyleneamino)-4-[6-(3-methylureido)30 methylpyridin-2-yl]thiazole dihydrochloride mp : 238-239°C IR (Nujol) : 3310, 1680, 1658, 1590 cm1 NMR (DMSO-dg, δ) : 2.62 (3H, s), 4.53 (2H, s), 7.59 (1H, d, J=7.0Hz), 8.24 (1H, t, J=7.0Hz), 8.35 (1H, d, J=7.0Hz), 8.44 (1H, s), 8.50 (4H, s) Anal. Calcd. for C12H15N7OS’2HC1 : C 38.10, H 4.53, N 25.92, Cl 18.74 Found : C 37.95, H 4.35, N 25.62, Cl 18.30 Example 24 A mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole trihydrochloride {1.7 g), triethylamine (2.0 ml) and 1,1-bis(methylthio)-2nitroethylene (0.9 g) was stirred at 70°C for 7 hours.

After cooling to ambient temperature, to the mixture was added a 40% aqueous methylamine (2.5 ml) and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was added to water, and the isolated precipitate was collected by filtration and dried. 4N-Dioxanoic hydrogen chloride (2.2 ml) was added to a mixture of above resulting precipitate in methanol (9.0 ml) and the mixture was stirred at ambient temperature for 1 hour. To the mixture was added a diisopropyl ether (9.0 ml) and the isolated precipitate was collected by filtration. The precipitate was recrystallized from an aqueous ethanol to give 2-(diaminomethyleneamino)-4-(6-(N(1-methylamino-2-nitrovinyl)aminomethyl]pyridin-2-yl]thiazole (0.47 g). mp : 184-185°C (dec.) IR (Nujol) : 3180, 1700, 1635, 1560 era'1 NMR (DMSO-dg + D2O, δ) : 2.84 (3H, s), 4.62 (2H, s), 7.37 (1H, d, J=7.5Hz), 7.95 (1H, t, J=7.5Hz), 8.00-8.10 (2H, m) Anal. Calcd. for c13H16N8O2S*1HCl'1-1H2° : C 38.59, H 4.78, Ν 27.69, Cl 8.76, H20 4.90 Found : C 38.23, H 4.71, N 27.22, Cl 8.47, H2O 4.77 Example 25 A mixture of 4-(6-aminomethylpyridin-2-yl)-235 (diaminomethyleneamino)thiazole trihydrochloride (1.5 g), triethylamine (1.8 ml) and dimethyl N-methanesulfonyldithiocarbonimidate (0.8 g) in ethanol (30 ml) was heated under reflux for 5 hours. The solvent was removed by concentration in vacuo. To the residue was added to a mixture of 40% aqueous methylamine (4.0 ml) in Ν,Ν-dimethylformamide (13 ml) and the mixture was stirred at ambient temperature for 30 hours. The reaction mixture was added a water and the isolated precipitate was collected by filtration to give 2-(diaminomethyleneamino)10 4-(6-(2-methanesulfonyl-3-methylguanidino)methylpyridin2-yl]thiazole (1.12 g). mp : 254-255°C IR (Nujol) : 3425, 3340 , 3300, 3230, 1630, 1603, 1575, 1545 cm 1 15 NMR (DMSO-dg, δ) : 2.78 (6H, s), 4.50 (2H, d, J=4.7HZ) , 6.92 (4H, s), 7.15-7.21 (2H, m), 7.60 (IH, br s), 7.83-7.89 (2H, m) Example 26 The following compound was obtained according to a similar manner to that of Example 18. 2-(Diaminomethyleneamino)-4-[6-(2-methanesulfonyl-3methylguanidino)methylpyridin-2-yl]thiazole hydrochloride. mp : 197°C IR (Nujol) : 3320, 3280, 3230, 3100 z 1675, 1650, 1605, 1575, 1550 cm1 NMR (DMSO-dg, δ) : 2.79 (6H, s), 4. 54 (2H, d, J=4.6Hz), 7.15· -7.35 (IH, m), 7. 29 (IH, d, 30 J=7.7Hz), 7.91 (IH, d, J=7.7Hz) z 8.00-8.20 (IH, m), 8.09 (IH, d, J=7.7Hz), 8.36 (4H, s), 12.69 (IH, s) Anal. Calcd. for ci3H!8N8°2S2-HCI.1/2H2O : C 36.49, H 4.71, N 26.19, Cl 8.28, H2O 2.10 Found : C 36.23, H 4.63, N 26.11, Cl 8.28, H2O 2.02 Example 27 A mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole trihydrochloride (3.0 g), triethylamine (3.5 ml) and ethyl ethanesulfonylformimidate (1.5 g) in methanol (60 ml) was stirred at ambient temperature for 6.5 hours and after solvent was removed by concentration in vacuo. To the residue was added a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(620 ethanesulfonyliminomethylaminomethylpyridin-2-yl) thiazole (0.88 g). mp : 201°C IR (Nujol) : 3390, 3270, 1640, 1620, 1545 cm1 NMR (DMSO-d6, δ) : 1.10 (3H, t, J=7.3Hz), 2.92 (2H, q, J=7.3Hz), 4.59 (2H, d, J=5.4Hz), 6.94 (4H, s), 7.25 (IH, m), 7.53 (IH, s), 7.84 (2H, d, J=4.5Hz), 8.15 (IH, d, J=4.9Hz), 9.19 (IH, m) Anal. Calcd. for ci3Hi7N7°2S2 : C 42.49, H 4.66, N 26.68 Found : C 42.27, H 4.52, N 26.50 Example 28 A mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole trihydrochloride (1.5 g), triethylamine (1.8 ml) and l-amino-2-ethoxy-192 cyclobutene-3,4-dione (0.65 g) in methanol (30 ml) was heated under reflux for 7 hours. The solvent was removed by concentration in vacuo. To the residue was added a mixture of water and ethyl acetate, and the mixture was adjusted to pH 1.0 with 6N-hydrochloric acid. The isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from an aqueous Ν,Ν-dimethylformamide to give 4-[6-(l-amino-3,4-dioxo-lcyclobuten-2-y1)aminomethylpyridin-2-y1]-210 (diaminomethyleneamino)thiazole hydrochloride (1.17 g). mp : 271°C (dec.) IR (Nujol) : 3300, 1695, 1635, 1600 cm-1 NMR (DMSO-dg, δ) : 4.87 (2H, d, J=6.0Hz), 7.36 (1H, d, J=7.3Hz), 7.83 (2H, s), 7.91 (1H, t, J=7.3Hz), 7.98 (1H, s), 8.06 (1H, d, J=7.3Hz), 8.27 (4H, s), 8.42 (1H, t, J=6.0Hz) Anal. Calcd. for <2ΐ4Ηΐ31ί7θ25*^^’2Η2Ο : C 40.44, H 4.36, N 23.58, Cl 8.53, H.,0 8.66 Found : C 40.75, H 4.07, N 23.61, Cl 7.99, H2O 8.80 Example 29 A mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole trihydrochloride (3.0 g), triethylamine (3.5 ml) and diphenyl N-cyanocarbonimidate (2.0 g) in methanol (45 ml) was stirred at ambient temperature for 4 hours. After the solvent was evaporated in vacuo. Acetonitrile (45 ml) and methylhydrazine (2.2 ml) was added to a residue and the mixture was stirred at ambient temperature for 4 hours. The solvent was evaporated in vacuo. To the residue was added a mixture of water and ethyl acetate and the mixture was adjusted to pH 2 with 6N-hydrogen chloride. The separated aqueous layer was adjusted to pH 11 with 4N-sodium hydroxide, the isolated precipitate was collected by filtration and dried to give 4-[6-(3-amino-l-methyl-lH-l,2,4-triazol-5-yl)aminomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (2.71 g). mp : 260°C (dec.) IR (Nujol) : 3310, 3130, 1605, 1540 cm1 NMR (DMSO-dg, δ) : 3.38 (3H, s), 4.47 (2H, d, J=6.0Hz), 4.80 (2H, s), 6.84 (IH, t, J=6.0Hz), 6.93 (4H, s), 7.23 (IH, t, J=4.7Hz), 7.40 (IH, s), 7.73-7.80 (2H, m) Example 3 0 The following compound was obtained according to a 10 similar manner to that of Example 18. 4-[6-(3-Amino-l-methyl-lH-l,2,4-triazol-5-yl)aminomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole dihydrochloride mp : 193°C (dec.) IR (Nujol) : 3300, 3110, 1675, 1650, 1625, 1570 cm-1 NMR (DMSO-dg, δ) : 3.56 (3H, s), 4.69 (2H, d, J=5.6Hz), 7.41 (IH, d, J=7.5Hz), 7.80 (IH, s), 7.90 (IH, t, J=7.5Hz), 8.10 (IH, d, J=7.5Hz), 8.44 (4H, s) / 8.97 (IH, t, J =5. 6Hz) Anal. Calcd. for c 13H16N10S’2HCl : c 37.42, H 4.35, N 33.56, Cl 16.99 Found : c 37.03, H 4.09, N 33.19, Cl 16.74 Example 31 A suspension of 4-[(2-acetylamino-l-iminoethylthio)acetyl]-2- (diaminomethyleneamino) thiazole hydrobromide (11.4 g) in ethanol (100 ml) was refluxed for 2.5 hours. The resulting precipitate was collected by filtration and suspended in water (150 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from water afforded 4-(2-acetylaminomethylthiazol-4-yl)-235 (diaminomethyleneamino)thiazole (6.36 g).

IR (Nujol) : 3250, 1640 cm x Example 3 2 The following compound was obtained from 5 4-bromoacetyl-2-(diaminomethyleneamino) thiazole hydrobromide according to a similar manner to that of the latter of Example 9. 2-(Diaminomethyleneamino)-4-(2-N,N-dimethylaminomethylthiazol-4-yl) thiazole. mp : 205-208°C IR (Nujol) : 3410, 3120, 1660, 1610 cm-1 NMR (DMSO-dg, δ) : 2.29 (6H, s), 3.76 (2H, s), 6.89 (4H, s), 7.01 (1H, s), 7.83 (1H, s) Example 33 A solution of 4N-dioxanic hydrogen chloride (1 ml) was added to a solution of 2-(diaminomethyleneamino)-4-(2N,N-dimethylaminomethylthiazol-4-yl)thiazole (0.28 g) in methanol (4 ml) and the mixture was stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-(diaminomethyleneamino)-4-(2-N,N-dimethylaminomethylthiazol-4-yl)thiazole dihydrochloride (0.21 g). mp : 285-286°C (dec.) IR (Nujol) : 3420, 3280, 1680, 1610 cm'1 NMR (DMSO-dg, δ) : 2.85 (6H, s), 4.73 (2H, s), 7.63 (1H, s), 8.30 (4H, s), 8.50 (1H, s) Anal. Calcd. for ciq^14N6S2’2HC1 : C 33.80, H 4.54, N 23.65, Cl 19.96 Found : C 33.53, H 4.47, N 23.35, Cl 19.97 Example 34 The following compound was obtained from 4-bromoacetyl-2-(diaminomethyleneamino)thiazole according to a similar manner to that of the latter of Example 9. 2-(Diaminomethyleneamino)-4-[2-(3-isopropylureido) methylthiazol-4-yl]thiazole mp : 249°C (dec.) IR (Nujol) 3420, 3370, 3110, 1630 cm NMR (DMSO-dg, fi) : 1.06 (6H, d, J=6.5Hz), 3.78-3.62 (1H, m), 4.48 (2H, ed, J=6.lHz), 6.06 (1H, d, J=7.8Hz), 6.57 (1H, t, J=6.lHz), 6.90 (4H, s), 7.01 (1H, s), 7.75 (1H, s) Anal. Calcd. for ci2Hi7N7OS2 : C 42.46, H 5.05, N 28.89 Found : C 42.56, H 4.94, N 29.13 Example 35 A suspension of 4-(2-aminomethylthiazol-4-yl)-2(diaminomethyleneamino)thiazole dihydrochloride (1.6 g), (furfurylthio)acetic acid (0.98 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 20 hydrochloride (1.2 g) and triethylamine (1.0 g) in Ν,Ν-dimethylformamide (20 ml) was stirred with cooling on an ice-water bath for 2.5 hours. The solvent was removed under the reduced pressure. The residue was washed with water and then chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). The appropriate fractions was collected and the solvent was removed under the reduced pressure. The residue was suspended in water (20 ml) and the mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 2-(diaminomethyleneamino)-4-[2(furfurylthio)acetylaminomethylthiazol-4-yl]thiazole (0.22 g) · mp : 204°C IR (Nujol) : 3400, 3180, 1680, 1625, 1605 cm NMR (DMSO-dg, δ) : 3.20 (2H, s), 3.89 (2H, s), 4.58 (2H, d, J=6.0Hz), 6.29 (IH, d, J=3.1Hz), 6.40 (IH, dd, J=l.l and 3.1Hz), 6.89 (4H, s), 5 7.02 (IH, s), 7.59 (IH, d, J=l.lHz), 7.81 (IH, s), 8.95 (IH, t, J=6.0Hz) Anal. Calcd. for C, r-H. cNr0oSo : 16 6 2 3 C 44.10, H 3.95, N 20.57 Found : C 43.85, H 3.93, N 20.31 Example 36 A suspension of 4-(2-aminomethylthiazol-4-yl)-2(diaminomethyleneamino) thiazole dihydrochloride (1.0 g), dimethyl N-cyanodithiocarbonimidate (0.45 g) and triethyl amine (0.7 g) in Ν,Ν-dimethylformamide (40 ml) was heated at 70°C for 10 hours. 40% methylamino solution (5 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml) and the mixture was alkalized to pH 10 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of Ν,Ν-dimethylformamide and water afforded 2-(diaminomethyleneamino)-4-[2-(225 cyano-3-methylguanidino)methylthiazol-4-yl]thiazole (0.2 g) · mp : 244-250°C (dec.) IR (Nujol) : 3460, 3220, 2140, 1640 cm'1 NMR (DMSO-dg, δ) : 2.73 (3H, d, J=4.7Hz), 4.62 (2H, d, J=5.9Hz), 6.89 (4H, s), 7.02 (IH, s), 7.34 (IH, q, J=4.7Hz), 7.81 (IH, s), 7.88 (IH, t, J=5.9Hz) Anal. Calcd. for cnHi3N9S2* : C 36.82, H 4.38, N 35.13, H2O 6.53 Found : C 37.20, H 4.27 , N 34.85, H2O 6.17 Example 37 A suspension of 4-(2-aminomethylthiazol-4-yl)-ΣΙ diaminomethyleneamino) thiazole dihydrochloride (1.3 g), ethyl ethanesulfonylformimidate (0.8 g) and triethylamine (1.0 g) in methanol (20 ml) was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from a mixture of Ν,Ν-dimethylformamide and water afforded 2-(diaminomethyleneamino)-4-(2-ethanesulfonyliminomethylaminomethylthiazol-4-yl)thiazole (0.53 g). mp : 216-217°C IR (Nujol) : 3420, 3120, 1645, 1605 cm1 NMR (DMSO-dg, δ) : 1.11 (3H, t, J=7.3Hz), 2.95 (2H, q, J=7.3Hz), 4.78 (2 Ή, s) , 6.90 (4H, s), 7.04 (IH, s), 7. 87 (IH, 8.14 (IH, s), 9.40 (IH, s) Anal. Calcd forC11H15N7°2S3 : C 35.38, H 4.05, N 26. .25 Found : C 35.42, H 3.98, N 26. .31 Example 38 The following compound was obtained according to a 25 similar manner to that of Example 18. 4-(6-Aminomethylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole trihydrochloride mp : 288-289°C IR (Nujol) : 3375, 3275, 3175, 1685 cm1 NMR (DMSO-dg, δ) : 4.25 (2H, q, J=5.8Hz), 6.12 (3H, br s), 7.46 (IH, d, J=7.7Hz), 7.95 (IH, t, J=7.7Hz), 8.18 (IH, d, J=7.7Hz), 8.33 (IH, s), 8.41 (4H, s) and 8.62 (2H, br s) Anal. Calcd. for c1oH12N6S*3HCl’1/3H2° : C 33.02, H 4.34, N 23.11 Found : C 33.16, H 4.09, N 22.89 Example 39 A mixture of 2-(diaminomethyleneamino)-4-(6propionylaminomethylpyridin-2-yl)thiazole {49.0 g) and cone, hydrochloride acid (134 ml) in ethanol (500 ml) was heated under reflux for 7 hours and after the mixture was cooled to ambient temperature. To the mixture was added ethanol (500 ml) with stirring and the isolated precipitate was collected by filtration to give 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (52.36 g).

IR (Nujol) : 3375, 3275, 3175, 1685 cm-1 Example 40 A mixture of formic acid (0.47 ml) and acetic anhydride (0.87 ml) was stirred at 40-50°C for 30 minutes.

To a mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole trihydrochloride (3.0 g) and triethylamine (3.5 ml) in Ν,Ν-dimethylformamide (45 ml) was added the above mixture under ice-cooling and the mixture was stirred at ambient temperature for 5 hours.

The reaction mixture was added to water and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on alumina, eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from an aqueous methanol to give 2-(diaminomethyleneamino)-435 (6-formylaminomethylpyridin-2-yl)thiazole (0.62 g). mp : 192-193°C IR (Nujol) : 3-420, 3350, 1685, 1605, 1590 cm'1 NMR (DMSO-dg, δ) : 4.43 (2H, d, J=5.9Hz), 6.93 (4H, s), 7.17-7.23 (1H, m), 7.47 (1H, s), 7.79-7.85 (2H, m), 8.21 (1H, s), 8.63 (1H, m) Anal. Calcd. for -N-OS : 12 6 C 47.82, H 4.38, N 30.41 Found : C 47.63, H 4.21, N 30.05 Example 41 Trifluoroacetic anhydride (2.4 ml) was added to a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole trihydrochloride (3.0 g) and triethylamine (4.7 ml) in Ν,Ν-dimethylformamide (60 ml) under ice-cooling, and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-trifluroacetylaminomethylpyridine-2-yl)thiazole (0.74 g). mp : 271°C (dec.) IR (Nujol) : 3430, 3320, 1705, 1650, 1605, 1540 cm NMR (DMSO-dg, δ) : 4.54 (2H, d, J=5.8Hz), 6.94 (4H, s), 7.18 (1H, t, J=4.3Hz), 7.35 (1H, s), 7.83 (2H, d, J=4.3Hz), 10.05 (1H, t, J=5.8Hz) Anal. Calcd. for ^i2^11Ii6<3^F3 : C 41.86, H 3.22, N 24.41 Found : C 41.71, H 3.16, N 24.11 100 Example 42 The following compound was obtained according to a similar manner to that of Example 41. 2-(Diaminomethyleneamino)-4-(6-butyrylaminomethylpyridin-2-yl) thiazole mp : 233-234°C IR (Nujol) : 3370, 1660, 1610, 1550 cm1 NMR (DMSO-dg, δ) : 0.89 (3H, t, J=7.4Hz), 1.0 1.49-1.67 (2H, m) , 2.19 (2H, t, J=7.2Hz), 4.39 (2H, d, J=5.9Hz), 6.94 (4H, s), 7.17-7.19 (1H, m), 7.41 (1H, s), 7.78-7.84 (2H, m), 8.41 (1H, t, J=5.9Hz) Anal. Calcd. for C..H.oNc0S : 18 6 C 52.81, H 5.70, N 26.39 Found : C 52.60, H 5.67, N 26.18 Example 43 To a mixture of 4-(6-aminomethylpyridin-2-yl)-220 (diaminomethyleneamino)thiazole trihydrochloride (3.0 g) and triethylamine (4.7 ml) in Ν,Ν-dimethylformamide (60 ml) was added a methoxyacetyl chloride (0.9 ml) under ice-cooling and the mixture was stirred for 2.5 hours at the same temperature. The reaction mixture was added to ?5 water and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-methoxyacetylaminomethylpyridin-2-yl)thiazole (0.86 g). mp : 195-196°C IR (Nujol) : 3390, 1665, 1560 cm-1 NMR (DMSO-dg, δ) : 3.38 (3H, s), 3.93 (2H, s), 4.44 (2H, d, J=5.9Hz), 6.93 (4H, s), 101 7.16 (IH, t, J=4.5Hz), 7.37 (1H, s), 7.79 (2H, d, J=4.5Hz), 8.44 (IH, t, J=5.9Hz) Anal. Calcd. for C.oHncNc0-S : 16 6 2 C 48.74, H 5.03, N 26.23 5 Found : C 48.53, H 4.98, N 26.37 Example 44 The following compound was obtained according to a similar manner to that of Example 21. 4-(6-Cyclopropylcarbonylaminomethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole mp : 219°C IR (Nujol) : 3410, 3290, 1645, 1590 cm NMR (DMSO-d6' δ) : 0.68-0.80 (4H, m) , 1.64-1.77 (IH, m) , 4 .41 (2H, d, J=5.8Hz), 6.94 (4H, s), 7.16 (IH, t, J=4.7Hz), 7.43 (IH, s), 7.80 (2H, d, J=4.7Hz), 8.68 (IH, t, J=5.8Hz) Anal. Calcd. for C^^H^^NgOS : C 53.15, H 5.10, N 26.56 Found : C 52.90, H 5.00, N 26.52 Example 45 The following compound was obtained according to a similar manner to that of Example 43. 4-[6-(2-Acetyloxy)propionylaminomethylpyridin-2-y1]2-(diaminomethyleneamino) thiazole mp : 187°C IR (Nujol) : 3410, 3290, 1730, 1660, 1605 cm1 NMR (DMSO-dg, δ) : 1.40 (3H, d, J=6.9Hz), 2.09 (3H, s), 4.41 (2H, d, J=5.9Hz), .04 (IH, q, J=6.9Hz), 6.93 (4H, s), 7.10-7.20 (IH, m), 7.40 (IH, s), 7.79 (2H, d, J=5Hz), 8.65 (IH, t, J=5.9Hz) 102 Anal. Calcd. for ci5HigN6O3S ’ C 49.71, H 5.01, N 23.19 Found : C 49.71, H 4.97, N 22.90 Example 46 The following compound was obtained according to a similar manner to that of Example 43. 2-(Diaminomethyleneamino)-4-[6-(2-furoyl) amino10 methylpyridin-2-yl)thiazole mp : 220-221°C (dec.) IR (Nujol) : 3390, 3360, 1655, 1615, 1600, 1550 cm1 NMR (DMSO-dg, δ) : 4.56 (2H, d, J=6.0Hz), 6.66 (1H, dd, J=1.8Hz and 3.4Hz), 6.97 (4H, s), 7.16-7.21 (2H, m), 7.38 (1H, s), 7.78-7.83 (2H, m), 7.88 (1H, s), 9.00 (1H, t, J=6.0Hz) Example 47 The following compound was obtained according to a 20 similar manner to that of Example 18. 2-(Diaminomethyleneamino)-4-[6-(2-furoyl)aminomethylpyridin-2-yl]thiazole dihydrochloride mp : 157-158°C IR (Nujol) : 3380, 1690, 1600, 1565 cm1 NMR (DMSO-dg, δ) : 4.73 (2H, d, J=5.9Hz), 6.67 (1H, dd, J=1.8Hz and 3.5Hz), 7.26 (1H, d, J=3.5Hz), 7.48 (1H, d, J=7.8Hz), 7.91 (1H, s), 8.09 (1H, t, J=7.8Hz), 8.22 (1H, s), 8.25 (1H, d, J=7.8Hz), 8.48 (4H, s), 9.24 (1H, t, J=5.9Hz) Anal. Calcd. for C15H14NgO2S«2HCl«13/10H2O : C 41.06, H 4.27, N 19.16, Cl 16.16, H20 5.34 Found : C 41.04, H 4.33, N 19.02, Cl 16.21, H2O 5.06 103 Example 48 The following compound was obtained according to a similar manner to that of Example 21. 2-(Diaminomethyleneamino)-4-(6-nicotinoylaminomethylpyridin-2-yl)thiazole mp : 239°C (d ec. ) IR (Nujol) : 3350, 1650, 16 10, 1590 cm1 NMR (DMSO-dg, δ) : 4.64 (2H :, d, J=5.7Hz), 6.94 (4H, s), 7.25 (IH, m), 7.39 (IH, s) , '7.55 (IH, dd, J=4.9Hz a nd 7.7Hz), 7.81 (2H, d, J=4.0Hz), 8.28 (IH, d, J= =7.7Hz) 8.74 (IH, d, J=4.9Hz), 9.11 (IH, s), 9.36 (IH, t, J=5.7Hz) Ana 1. Calcd. f or C^gH^gN^OS C 54.38, H 4.28, N 27.74 Found : C 54.31, H 4.29, N 27.41 Example 49 The following compound was obtained according to a similar manner to that of Example 43. 2-(Diaminomethyleneamino)-4-[6-(1,1-dioxobenzoisothiazol-3-yl)aminomethylpyridin-2-yl]thiazole mp : 265°C IR (Nujol) : 3330, 1655, 1615, 1590 cm1 NMR (DMSO-dg, δ) : 4.83 (2H, d, J=5.5Hz), 6.93 (4H, s), 7.30-7.34 (IH, ro), 7.39 (IH, s), 7.80-7.88 (4H, m), 7.97-8.03 (IH, m), 8.27-8.32 (IH, m), 10.07 (IH, t, J=5.5Hz) Example 50 The following compound was obtained according to a similar manner to that of Example 18. 104 2-{Diaminomethyleneamino)-4-(6-(1,1-dioxobenzoisothiazol-3-yl)aminomethylpyridin-2-y1]thiazole hydrochloride mp : 303°C (dec.) IR (Nujol) : 3300, 1690, 1610, 1590 cm'1 NMR (DMSO-dg, δ) : 4.86 (2H, d, J=5.6Hz), 7.42 (1H, d, J=7.6Hz), 7.85-8.03 (5H, m), 8.11 (1H, d, J=7.6Hz), 8.35 (4H, m), 8.30-8.45 (1H, m), 10.34 (1H, t, J-5.6Hz), 12.66 (1H, s) Anal. Calcd. for cx7Hi5N7°2S2’HCl : C 45.38, H 3.58, N 21.79, Cl 7.88 Found : C 45.13, H 3.43, N 21.50, Cl 7.71 Example 51 The following compound was obtained according to a similar manner to that of Example 22. 2-(Diaminomethyleneamino)-4-(6-(3-ethylureido)20 methylpyridin-2-yl]thiazole mp : 219°C IR (Nujol) : 3330, 1630, 1600 cm1 NMR (DMSO-dg, δ) : 1.02 (3H, t, J=7.2Hz), 2.99-3.12 (2H, m), 4.32 (2H, d, J=5.7Hz), 6.18 (1H, t, J=5.5Hz), 6.46 (1H, t, J=5.7Hz), 6.94 (4H, s), 7.14-7.21 (1H, m), 7.46 (1H, s), 7.74-7.83 (2H, m) Example 52 The following compound was obtained according to a similar manner to that of Example 18. 2-(Diaminomethyleneamino)-4-(6-(3-ethylureido)methylpyrdin-2-yl]thiazole dihydrochloride mp : 229°C 105 IR (Nujol) : 3320, 3220, 1685, 1590 cm A NMR (DMSO-dg, δ) : 1.03 (3H, t, J=7.2Hz), 3.08 (2H, g, J=7.2Hz), 4.54 (2H, s) , 7.59 (IH, d, J=7.1Hz), 8.25 (IH, t, J=7.1Hz), 5 8.36 (IH, d, J=7.1Hz), 8.45 (IH, s), 8.50 (4H, s) Anal. Calcd. for C,3H,7N7OS •2HC1 • C 39.80, H 4.88, N 24 .99, Cl 18.07 Found : C 39.52, H 4.74, N 24.74, Cl 17.92 Example 53 The following compound was obtained according to a similar manner to that of Example 18. 4-(6-Acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino ) thiazole hydrochloride mp : 260°C (dec.) IR (Nujol) : 3330, 3220 NMR (DMSO-dg, δ) : 1.94 20 J=5.9Hz), 7.26 (IH, J=7.5Hz), 7.93 (IH, 8.36 (4H, s), 8 .54 12.71 (IH, s) Anal. Calcd. for C-2H14N 25 C 40.52, H 5.16 Found : C 40.39, H 5.06, N 23.07, Cl 10.28, H2O 7.85 Example 54 The following compound was obtained according to a similar manner to that of Example 12. 4-(6-Acetylaminoraethylpyridin-2-yl)-2-(diaminomethyleneamino ) thiazole methanesulfonate mp : 242°C IR (Nujol) : 3300, 1700, 1630, 1580 cm’1 106 NMR (DMSO-dg, δ) : 1.94 (3H, s), 2.40 (3H, s), 4.39 (2H, d, J=5.9Hz), 7.26 (IH, d, J=7.3Hz), 7.86 (IH, t, J=7.3Hz), 7.93 (IH, s) , 8.00 (IH, d, J=7.3Hz), 8.28 (4H, s), 8.49 (IH, t, J=5.9Hz), 12.01 (IH, s) Anal. Calcd. for ci2H14N6OS’CH3SO3H : C 40.41, H 4.69, N 21.75 Found : C 40.44, H 4.39, N 21.49 Example 55 A mixture of 2-(diaminomethyleneamino)-4-[6-[(imino)(methoxy)methyl]pyridin-2-yl]thiazole (0.9 g) in 50% aqueous tetrahydrofuran (60 ml) was adjusted to pH 1.0 with 6N-hydrochloric acid and stirred for 5 minutes at ambient temperature. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-(6-methoxycarbonylpyridin-2yl)thiazole (0.54 g). mp : 240°C IR (Nujol) ; 3440, 3360, 1720, 1650, 1600 cm'1 NMR (DMSO-dg, δ) : 3.91 (3H, s), 6.94 (4H, s), 7.45 (IH, s), 7.93 (IH, dd, J=1.3Hz and 7.6Hz), 8.03 (IH, t, J=7.6Hz), 8.17 (IH, dd, J=1.3Hz and J=7.6Hz) Anal. Calcd. for cnHnN5O2S : C 47.65, H 4.00, N 25.26 Found : C 47.61, H 3.87, N 24.96 Example 56 The following compound was obtained according to a similar manner to that of Example 43. 107 2-(Diaminomethyleneamino)-4-(6-methoxycarbonylaminomethylpyridin-2-yl) thiazole mp : 217°C IR (Nujol) : 3420, 3390, 1705, 1640, 1610 cm-1 NMR (DMSO-dg, δ) : 3.59 (3H, s), 4.31 (2H, d, J=6.2Hz), 6.94 (4H, s), 7.13-7.22 (1H, m), 7.39 (1H, s), 7.74-7.85 (3H, m) Example 57 The following compound was obtained according to a similar manner to that of Example 18. 2-(Diaminomethyleneamino)-4-(6-methoxycarbonylaminomethylpyridin-2-yl) thiazole dihydrochloride mp : 188-189°C IR (Nujol) : 3340, 3210, 1675, 1605 cm-1 NMR (DMSO-dg, δ) : 3.59 (3H, s), 4.46 (2H, d, J=5.3Hz), 7.41 (1H, d, J=7.8Hz), 7.91 (1H, t, J=5.3Hz), 8.05 (1H, t, J=7.8Hz), 8.15 (1H, s), 8.20 (1H, d, J=7.8Hz), 8.44 (4H, s) Anal. Calcd. for C12H14NgO2S*2HCl«l/5H2O : C 37.65, H 4.32, N 21.95, Cl 18.52, H2O 0.94 Found : C 37.72, H 4.34, N 21.97, Cl 18.31, H2O 1.02 Example 58 Bromine (0.2 ml) was added dropwise to a mixture of 2-acetyl-6-dimethylaminomethylpyridine (0.7 g) in dioxane (20 ml) and 4N-dioxanichydrogen chloride (2 ml) at ambient temperature with stirring and then the mixture was stirred for 5 hours at 50°C. To the reaction mixture was added a diisopropyl ether (20 ml) at ambient temperature and isolated precipitate was collected by filtration. The resulting mixture was added a mixture of sodium bicarbonate (1.0 g) and diaminomethylenethiourea (0.7 g) in methanol (20 ml) and the mixture was stirred for 2.5 108 hours at 50-60°C. The solvent was removed by concentration in vacuo. To the residue was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 12 with 4N-sodium hydroxide. The separated organic layer was washed with brine and dried over magnesium sulfate. The mixture was concentrated and the residue was triturated with a mixture of ethyl acetate and diethyl ether to give 2-(diaminomethyleneamino)-4-(6dimethylaminomethylpyridin-2-yl)thiazole (0.49 g). mp : 160-162°C IR (Nujol) : 3400, 1650, 1590 cm'1 NMR (DMSO-dg, 0) : 2.22 (6H, s), 3.55 (2H, s), 6.92 (4H, s), 7.29-7.35 (IH, m), 7.35 (IH, s), 7.75-7.84 (2H, m) Example 59 The following compound was obtained according to a similar manner to that of Example 18. 2-(Diaminomethyleneamino)-4-(6-dimethylaminomethylpyridin-2-yl)thiazole trihydrochloride. mp : 266°C IR (Nujol) : 1680, 1625, 1590 cm1 NMR (DMSO-dg, δ) : 2.84 (3H, s), 2.86 (3H, s), 4.54 (2H, d, J=4.9Hz), 7.54 (IH, d, J=7.8Hz), 7.99 (IH, t, J=7.8Hz), 8.24 (IH, d, J=7.8Hz), 8.36-8.60 (5H, m) Anal. Calcd. for C^K^NgS· 3HC&· 1/2^0 : C 36.51, H 5.11, N 21.29, Cl 26.94, H20 2.28 Found : C 36.38, H 5.07, N 21.11, Cl 26.81, H20 2.30 Example 60 The following compound was obtained according to a similar manner to that of Example 17. 109 4-(6-Carbamoylpyridin-2-y1)-2-(diaminomethyleneamino) thiazole mp : 269°C IR (Nujol) : 3420, 3350, 3250, 1655, 1620 cm”1 NMR (DMSO-dg, δ) : 6.96 (4H, s), 7.71 (1H, s), 7.92 (1H, dd, J=1.3Hz and 7.5Hz), 8.01 (1H, t, J=7.5Hz), 8.07 (1H, dd, J=1.3Hz and 7.5Hz), 8.44 (1H, s) Example 61 The following compound was obtained according to a similar manner to that of Example 18. 4-(6-Carbamoylpyridin-2-yl)-2-(diaminomethylene15 amino)thiazole hydrochloride mp : 310°C (dec.) IR (Nujol) : 3290 (br), 1675, 1610, 1585, 1560 cm1 NMR (DMSO-dg, δ) : 7.79 (1H, s), 8.01 (1H, dd, J=1.4Hz and 7.7Hz), 8.09 (1H, t, J=7.7Hz), 8.28-8.45 (5H, m), 8.58 (2H, s) Anal. Calcd. for C^QH^QNgOS«HCl : C 40.20, H 3.71, N 28.13, Cl 11.87 Found : C 40.01, H 3.92, N 27.92, Cl 11.56 Example 62 Phosphorus oxychloride (0.7 ml) was dropwise added to a mixture of 4-(6-carbamoylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole (1.0 g) in Ν,Ν-dimethylformamide (10 ml) at 2-8°C with stirring and the mixture was stirred for 5 hours at the same temperature. The reaction mixture was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate.

The solvent was removed by concentration and the residue 110 was triturated with a mixture of ethyl acetate and ether to give 4-(6-cyanopyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.84 g). mp : >300°C IR (Nujol) 3450, 3420, 2240, 1650, 1600, 1580 cm1 NMR (DMSO-dg, δ) : 6.95 (4H, s), 7.56 (IH, s), 7.90 (IH, dd, J=l.lHz and 7.7Hz), 8.08 (IH, t, J=7.7Hz), 8.25 (IH, dd, J=l.lHz and 7.7Hz) Example 63 To a solution of 4-(6-cyanopyridin-2-yl)-2(diaminomethyleneamino)thiazole (0.7 g) in dry chloroform (7 ml) and dry methanol (14 ml) was bubbled with dry hydrogen chloride for 30 minutes under ice-cooling and the mixture was stirred for 1.5 hours at the same temperature. To the reaction mixture was added diisopropyl ether (20 ml) under stirring and the isolated precipitate was collected by filtration. The precipitate was made basic to pH 9.5 with an aqueous potassium carbonate under ice-cooling. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was triturated with diisopropyl ether to give 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (0.64 g). mp : 208-210°C IR (Nujol) : 3310, 1645, 1600, 1575 cm1 NMR (DMSO-dg, δ) : 3.92 (3H, s), 6.95 (4H, s), 7.70 (IH, dd, J=1.2Hz and 7.5Hz), 7.78 (IH, s), 7.99 (IH, t, J=7.5Hz), 8.07 (IH, dd, J=1.2Hz and 7.5Hz) Example 64 A mixture of 2-(diaminomethyleneamino)-4-[6111 ( imino)(methoxy)methylpyridin-2-yl]thiazole (2.1 g) and sulfamide (2.9 g) in 2-methoxyethanol (10.5 ml) was stirred for 3 hours at 70-75°C. The mixture was added to water, isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from a mixture of Ν,Ν-dimethylformamide and ethyl acetate to give 4-[6-(amino)(aminosulfonylimino)methylpyridin-2-yl]-2(diaminomethyleneamino)thiazole (1.28 g). mp : 223-224°C (dec.) IR (Nujol) : 3440, 3360, 3320, 1630, 1585 cm-1 NMR (DMSO-dg, δ) : 6.88 (4H, s), 6.93 (2H, s), 7.70 (1H, s), 7.96-8.08 (3H, m) , 8.13 (1H, dd, J=2.6Hz and 6.5Hz), 8.98 (1H, s) Anal. Calcd. for ciqhi2N8°2^2 ’ 3//3H2° : C 34.20, H 3.79, N 31.91, Η?Ο 3.08 Found : C 34.45, H 3.58, N 31.71, H2O 3.23 Example 65 Bromine (0.64 ml) was added to a mixture of 2-acetyl20 6-cyanomethylpyridine (2.0 g) in dioxane (30 ml) and 4N-dioxanichydrogen chloride (3.1 ml) at ambient temperature with stirring, and then the mixture was stirred for 1 hour at 50°C. To the mixture was added the sodium bicarbonate (5.2 g), methanol (30 ml) and diaminomethylenethiourea (2.2 g) at ambient temperature and the mixture was stirred for 2.5 hours at 50°C. The solvent was removed by concentration in vacuo. To the residue was added a mixture of water, tetrahydrofuran and ethyl acetate and the mixture was adjusted to pH 9.5 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with water to give 4-(6-cyanomethylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole (1.5 g). mp : 216-217°C (dec.) 112 IR (Nujol) : 3400, 2250, 1655, 1595 cm A NMR (DMSO-dg, δ) : 4.23 (2H, s), 6.93 (4H, s), 7.26-7.35 (1H, m), 7.40 (1H, s), 7.83-7.91 (2H, m) Example 66 The following compound was obtained according to a similar manner to that of Example 63. 2-(Diaminomethyleneamino)-4-(6-(2-imino-2-methoxyethyl) pyr idin- 2-yl] thiazole mp : 172-173°C IR (Nujol) : 3310, 1650, 1590 cm1 NMR (DMSO-dg, δ) : 3.60 (3H, s), 3.74 (2H, s), 6.92 (4H, s), 7.12-7.30 (1H, m), 7.36 (1H, s), 7.75-7.82 (2H, m), 8.13 (1H, s) Example 67 The following compound was obtained according to a 20 similar manner to that of Example 64. 4-(6-(2-Amino-2-(aminosulfonylimino) ethyl]pyridin-2yl]-2-(diaminomethyleneamino)thiazole mp : 207-208°C IR (Nujol) : 3420, 3350, 3230, 1650, 1600 cm1 NMR (DMSO-dg, δ) : 3.71 (2H, s), 6.56 (2H, s), 6.92 (4H, s), 7.20-7.30 (1H, m), 7.42 (1H, s), 7.48 (1H, s), 7.75-7.83 (2H, m), 8.42 (1H, s) Anal. Calcd. for C2.1H14N8°2S2 : C 37.28, H 3.98, N 31.62 Found : C 37.03 , H 3.97, N 31.33 Example 68 The following compound was obtained from 4-bromoacetyl-2-(diaminomethyleneamino) thiazole according 113 to a similar manner to that of the latter of Example 9. 4-[2-(2-t-Butoxycarbonylaminoethyl)thiazol-4-yl]2- (diaminomethyleneamino) thiazole mp : 197-198°C (dec.) IR (Nujol) : 3420, 3360, 1670, 1610 cm1 NMR (DMSO-dg, δ) : 1.37 (9H, s), 3.10 (2H, t, J=6.8Hz), 3.29 (2H, m), 6.91 (4H, s), 7.03 (2H, br), 7.76 (IH, s) Example 69 Hydrogen chloride gas was babbled to a solution of 4-(2-(2-t-butoxycarbonylaminoethyl)thiazol-4-yl]-2(diaminomethyleneamino)thiazole (3.0 g) in ethanol (30 ml) for 10 minutes at room temperature. The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was collected by filtration.

Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-[2-(2-aminoethyl)thiazol20 4-yl]-2-(diaminomethyleneamino)thiazole dihydrochloride (2.3 g). mp : 284-286°C (dec.) IR (Nujol) : 3350, 3120, 1680, 1610 cm1 NMR (DMSO-dg, δ) : 3.4-3.3 (4H, m), 7.67 (IH, s), 8.17 (4H, s), 8.29 (IH, s), 8.35 (3H, s), 12.69 (IH, s) Anal. Calcd. for CgH^2NgS2*2HC1 : C 31.67, H 4.13, N 24.63, Cl 20.78 Found : C 31.63, H 3.97, N 24.31, Cl 20.92 Example 70 A suspension of 4-(2-(2-aminoethyl)thiazol-4-yl]-2(diaminomethyleneamino) thiazole dihydrochloride (1.0 g), acetyl chloride (230 mg) and triethylamine (1.0 g) in Ν,Ν-dimethylformamide (30 ml) was stirred with cooling on 114 an ice-water bath for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution and then was extracted with ethyl acetate. The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with chloroform:methanol = 10:1 Recrystallization from a mixture of methanol, ethyl acetate and diisopropyl ether afforded 4-[2-(2acetylaminoethyl)thiazol-4-yl]-2-(diaminomethyleneamino)thiazole (0.33 g). mp : 226 to 227°C IR (Nujol) : 3420, 3280, 1670, 1620 cm'1 NMR (DMSO-dg, δ) : 1.81 (3H, s), 3.11 (2H, t, J=6.9Hz), 3.43-3.37 (2H, m), 6.89 (4H, s), 7.04 (IH, s), 7.76 (IH, s), 8.05 (IH, t, J=5.6Hz) Anal. Calcd. for C1^H^^NgOS2 : C 42.56, H 4.55, N 27.08 Found : C 42.66, H 4.39, N 26.89 Example 71 The following compound was obtained according to a similar manner to that of Example 11. 2-(Diaminomethyleneamino)-4-[2-(2-ureidoethyl)thiazol-4-yl]thiazole mp : 205-208°C (dec.) IR (Nujol) : 3320, 1680, 1650, 1610 cm-1 NMR (DMSO-dg, δ) : 3.11 (2H, t, J=6.7Hz), 3.40-3.20 (2H, m), 5.54 (2H, s), 6.15 (IH, t, J=6.0Hz), 7.59 (IH, s), 8.19 (IH, s), 8.25 (4H, s), 12.40 (IH, s) Anal. Calcd. for C10H13N7OS2-HCI·Η2Ο : C 32.83, H 4.13, N 26.80, Cl 9.69 Found : C 32.94, H 4.09, N 26.94, Cl 9.53 115 Example 72 The following compound was obtained according to a similar manner to that of Example 35. 4-{2-t-Butoxycarbonylaminoacetylaminomethylthiazol-4yl)-2-(diaminomethyleneamino)thiazole mp : 204°C (dec.) IR (Nujol) : 3410, NMR (DMSO-dg, 6) : J=5.9Hz), 4.57 7.02 (1H, s), s), 8.72 (1H, 3350, 3200, 1660, 1640, 1610 cm 1.39 (9H, s), 3.61 (2H, d, (2H, d, J=5.9Hz), 6.91 (4H, s), .08 (1H, t, J=5.9Hz), 7.95 (1H, , J=5.9Hz) Example 73 A solution of hydrogen chloride in dioxane (4N, 5 ml) was added slowly to a suspension of 4-(2-t-butoxycarbonylaminoacetylaminomethylthiazol-4-yl)2-(diaminomethyleneamino)thiazole (1.0 g) in methanol (5 ml) with cooling on an ice-water bath. The mixture was stirred for 24 hours with cooling on an ice-water bath.

The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-(2-aminoacetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino) thiazole dihydrochloride (0.58 g). mp : 275-277°C (dec.) IR (Nujol) : 3260, 1680, 1660, 1610 cm1 NMR (DMSO-dg, 5) : 3.65 (2H, d, J=5.2Hz), 4.68 (2H, d, J=5.9Hz), 7.57 (1H, s), 8.23 (3H, br), 8.32 ( 1H, s), 8.40 (4H, s), 9.41 (1H, t, J=5.9Hz) , 12.76 (1H, s) Anal. Calcd. for C1QH13N7OS2·2HC1-H2O C 29.85, H 4.26, N 24.37, Cl 17.62 Found : C 29.98, H 3.73, N 23.95, Cl 17.62 116 Example 74 The following compound was obtained according to a similar manner to that of Example 15. 4-(2-Cyanothiazol-4-yl)-2-(diaminomethyleneamino) thiazole mp : > 3 0 0 °C IR (Nujol) : 3460, 3350, 2220, 1640, 1610 cm'1 NMR (DMSO-dg, δ) : 7.27 (1H, s), 6.93 (4H, s) 8.47 (1H, s) Example 75 To a suspension of 4-(2-cyanothiazol-4-yl)-2(diaminomethyleneamino)thiazole (1.3 g) in dry methanol (15 ml) and dry dioxane (15 ml) was suspended with dry hydrogen chloride under ice-cooling and the mixture was stirred for 21 hours at the same temperature. The resulting precipitate was collected by filtration and then poured into a potassium carbonate solution (2.0 g in 20 ml). The resulting precipitate was collected by filtration to afford 2-(diaminomethyleneamino)-4-[2(imino)(methoxy)methylthiazol-4-yl]thiazole (1.06 g).

IR (Nujol) : 3430, 3400, 3310, 3110, 1640, 1600 cm'1 NMR (DMSO-dg, δ) : 3.90 (3H, s), 6.92 (4H, s), 7.22 (1H, s), 8.17 (1H, s), 9.05 (1H, s) Example 7 6 A suspension of 2-(diaminomethyleneamino)-4-[2(imino)(methoxy)methylthiazol-4-yl]thiazole (1.0 g) and sulfamide (1.36 g) in a 2-methoxyethanol (10 ml) was heated at 70°C for 7 hours. The resulting precipitate was removed by filtration. The filtrate was chromatographed on a silica gel column eluting with ethyl acetate:methanol = 3:1. Recrystallization from a mixture of Ν,Ν-dimethylformamide and water afforded 117 4-(2-1amino1(aminosulfonvlimino)methylthiazol-4-yl]-2(diaminomethyleneamino) thiazole (0.3 5 g). mp : >300°C IR (Nujol) : 3320, 1610 cm-1 NMR (DMSO-dg, δ) : 6.92 (4H, s), 6.99 (2H, s), 7.26 (IH, s), 7.72 (lH, s), 8.19 (IH, s), 8.77 (1H, s) Anal. Calcd. for C8HiQNgO2S2’H2° : C 26.70, H 3.22, N 31.13, H2O 3.75 Found : C 27.00, H 3.18, N 30.75, H?O 3.15 Example 77 Methanesulfonyl chloride (0.58 ml) was added a mixture of 4-(6-aminomethylpyridin-2-yl)-215 (diaminomethyleneamino)thiazole (1.8 g) and pyridine (0.81 ml) in dichloromethane (40 ml) under ice-cooling and the mixture was stirred for 23 hours at ambient temperature. The reaction mixture was added a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was recrystallized from an aqueous methanol to give 2-(diaminomethyleneamino)-4-(6-methanesulfonyl25 aminomethylpyridin-2-yl) thiazole (0.4 g). mp : 196°C IR (Nujol) : 3380, 1640, 1610 cm-1 NMR (DMSO-dg, δ) : 2.96 (3H, s), 4.31 (2H, s), 6.93 (4H, s), 7.31-7.41 (IH, m), 7.46 (IH, s), 7.66 (IH, s), 7.79-8.89 (2H, m) Example 78 The following compound was obtained according to a similar manner to that of Example 21. 118 2-(Diaminomethyleneamino)-4-(6-methylthioacetylaminomethylpyridin-2-yl)thiazole mp : 202°C IR (Nujol) : 3400, 1670, 1600 cm1 NMR (DMSO-dg, δ) : 2.14 (3H, s), 3.12 (2H, s), 4.42 (2H, d, J=5.8Hz), 6.92 (4H, s), 7.14-7.23 (1H, m), 7.42 (1H, s), 7.77-7.84 (2H, m) , 8.61 (1H, t, J=5.8Hz) Example 79 A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2[(amino)(methylthio)methyleneamino]thiazolehydriodide (2.0 g) and 30 wt % methylamine-methanol solution (2.0 g) in ethanol (40 ml) was refluxed for 27 hours. The solvent was removed by concentration and residue was added to a mixture of tetrahydrofuran, ethyl acetate and water. The mixture was adjusted to pH 9.5 with potassium carbonate and a separated organic layer was washed with brine, dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo.

The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)(methylamino)methyleneamino]thiazole (0.3 8 g). mp : 181°C IR (Nujol) : 3340, 3230, 3130, 1630, 1590 cm1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 2.77 (3H, d, J=4.8Hz), 4.37 (2H, d, J=5.9Hz), 7.14-7.21 (1H, m), 7.41 (1H, s), 7.46 (2H, s), 7.74-7.84 (2H, m), 8.45 (1H, t, J=5.9Hz) 119 Example 80 The following compound was obtained according to a similar manner to that of Example 79 excepting using ethylenediamine in place of 30 wt % methylamine-methanol. 4-(6-Acetylaminometylpyridin-2-yl)-2-(imidazolidin2-ylideneamino) thiazole mp : 248°C IR (Nujol) : 3300, 1640 cm-1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 3.55 (4H, s), 4.37 (2H, d, J=5.9Hz), 7.16 (IH, d, J=7.5Hz), 7.45 (IH, s), 7.66 (2H, s), 7.78 (IH, t, J=7.5Hz), 8.01 (IH, d, J=7.5Hz), 8.44 (IH, t, J=5.9Hz) Example 81 The following compound was obtained according to a similar manner to that of Example 79 excepting using 2,2,2-trifluoroethylamine in place of 30 wt % methylamine-methanol. 4-(6-Acetylaminomethylpyridin-2-yl)-2-[(amino)[(2,2,2-trifluoroethyl)amino]methyleneamino]thiazole mp : 233°C IR (Nujol) : 3380, 1650, 1620 cm-1 NMR (DMSO-dg, δ) : 1.93 (3H, s), 4.04-4.22 (2H, m), 4.38 (2H, d, J=5.9Hz), 7.10-7.27 (2H, m), 7.52 (IH, s), 7.73-7.88 (4H, m), 8.45 (IH, t, J=5.9Hz) Example 82 A solution of 4-(6-aminopyridin-2-yl)-2-(diaminomethyleneamino) thiazole dihydrochloride (5.0 g) in water (50 ml) was adjusted to pH 11 with 5N-sodium hydroxide and the mixture was extracted with a mixture of 120 tetrahydrofuran and ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-aminopyridin-2-yl)-2(diaminomethyleneamino) thiazole (3.6 2 g). mp : 242°C IR (Nujol) : 3330, 1660, 1605 cm1 NMR (DMSO-d6, δ) : 5.89 (2H, s), 6.37 (IH, d, J=7.7Hz), 6.92 (4H, s), 7.07 (IH, d, J=7.7Hz), 7.15 (IH, s), 7.41 (IH, t, J=7.7Hz) Example 83 A mixture of 4-(6-aminopyridin-2-yl)-2-(diaminomethyleneamino) thiazole (0.5 g) and methyl isocyanate (0.15 ml) in tetrahydrofuran (10 ml) was stirred for 30 hours at ambient temperature. Ethyl acetate (15 ml) was added to a reaction mixture and isolated precipitate was collected by filtration to give 2-((amino)(3-methylureido)methyleneamino)-4-(6-(3methylureido)pyridin-2-yl]thiazole (0.19 g).

IR (Nujol) : 337C i, 1670, 1620, 1595 cm1 NMR (DMSO- dg, δ) : 2.68 (3H, d, J=4.5Hz), 2.80 (3H, d, J=4.5Hz), 6.87 (IH, d, J=4.5Hz), 7.21 (IH, d, J=7.8Hz), 7.49 (IH, s), 7.56 (IH, d, J=7.8Hz), 7.73 (IH, t, J=7.8Hz), 25 8.31 (IH, d, J=4.5Hz), 8.87 (IH, br s), 9.31 (2H, s) The filtrate was evaporated in vacuo and the residue was triturated with diethyl ether to give 4-(6-amino30 pyridin-2-yl)-2-((amino)(3-methylureido)methyleneamino]thiazole (0.35 g).

IR (Nujol) : 3270 (br), 1610 (br) cm-1 NMR (DMSO-dg, δ) : 3.68 (3H, d, J=4.5Hz), 5.91 (2H, s), 6.40 (IH, d, J=7.5Hz), 7.16 (IH, d, J=7.5Hz), 7.37 (IH, s), 7.45 (IH, t, J=7.5Hz), 121 8.90 (1H, br s), 9.31 (1H, s) Example 84 The following compound was obtained according to a similar manner to that of Example 65. — [ 6 — ( 2-Cyanoethyl)pyridin-2-yl ] -7.- (diaminomethyleneamino ) thiazole mp : 218-220°C IR (Nujol) : 3430, 3250, 1650, 1595 cm1 NMR (DMSO-dg, δ): 2.93-3.01 (2H, m), 3.05-3.18 (2H, m), 6.95 (4H, m), 7.18-7.26 (IH, m), 7.47 (IH, s), 7.77-7.80 (2H, m) Example 85 A solution of pyridinium dichromate (3.2 g) in Ν,Ν-dimethylformamide (10 ml) was added dropwise to a solution of 2-(diaminomethyleneamino)-4-(6hydroxymethylpyridin-2-yl)thiazole (1.7 g) in 20 Ν,Ν-dimethylformamide (17 ml) at -10 ~ -5°C and the mixture was stirred for 5 hours at the same temperature. The reaction mixture was added to a mixture of ethyl acetate, tetrahydrofuran and water and the mixture was adjusted to pH 10 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-(diaminomethyleneamino)-4-(6-formylpyridin-2-yl)thiazole (0.31 g). mp : 287-289°C (dec.) IR (Nujol) : 3330 (br), 1700, 1600 cm-1 NMR (DMSO-dg, δ) : 6.95 (4H, s), 7.56 (IH, s), 122 7.81 (1H, d, J=7.0Hz), 8.08 (1H, t, J=7.0Hz), 8.23 (1H, d, J=7.0Hz), 10.01 (1H, s) Example 86 A mixture of 4-[6-(2-aminoethyl)pyridin-2-yl]-2(diaminomethyleneamino)thiazole trihydrochloride (1.5 g) and potassium cyanate (0.5 g) in water (30 ml) was stirred for 5 hours at ambient temperature. The reaction mixture was adjusted to pH 9.5 with potassium carbonate and the mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 2-(diaminomethyleneamino)-4-[6-(2ureidoethyl)pyridin-2-yl]thiazole (0.55 g).

IR (Nujol) : 3400, 3330, 1640, 1595 cm1 NMR (DMSO-dg, δ) : 2.86 (2H, t, J=6.9Hz), 7.34-7.45 (2H, m), 5.45 (2H, s), 5.96 (1H, t, J=5.7Hz), 6.93 (4H, s), 7.10-7.13 (1H, m), 7.40 (1H, S), 7.68-7.76 (2H, m) Example 87 The following compound was obtained according to a similar manner to that of Example 98. 2-(Diaminomethyleneamino)-4-[6-(1-methylcyanopropy1)carbonylaminomethylpyridin-2-yl]thiazole.

IR (Nujol) : 3390, 3330, 1655, 1630 cm1 NMR (DMSO-dg, δ) : 0.53-0.60 (2H, m), 0.98-1.06 (2H, m), 1.35 (3H, s), 4.40 (2H, d, J=5.8Hz), 6.93 (4H, s), 7.07-7.16 (1H, m), 7.37 (1H, s), 7.73-7.84 (2H, m), 8.18 (1H, t, J=5.8Hz) Example 88 The following compound was obtained according to a similar manner to that of Example 98. 123 4-> 6-Cyclopentylcarbonylaminomethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole IR (Nujol) : 3400, 3300, 1650, 1610 cm'1 A NMR (DMSO-dg, δ) : 1.40-1.95 (8H, m) , 2.60-2.75 (1H, m), 4.38 (2H, d, J=5.9Hz), 6.92 (4H, s), 7.08-7.18 (1H, m), 7.39 (1H, s), 7.73-7.85 (2H, m), 8.38 (1H, t, J=5.9Hz) Example 89 The following compound was obtained according to a similar manner to that of Example 98. 4-(6-Cyclohexylcarbonylaminomethylpyridin-2-yl)-215 (diaminomethyleneamino)thiazole IR (Nujol) : 3410, 3320, 3100, 1645, 1610 cm NMR (DMSO-dg, δ) : 1.06-1.92 (10H, m), 2.15-2.30 (1H, m), 4.36 (2H, d, J=5.9Hz), 6.93 (4H, s), 7.05- -7.17 (1H, m) , 7.39 (1H, s), 20 7.75-7.81 (2H, m), 8.32 (1H, t, J=5.9Hz) Example 90 The following compound was obtained according to a similar manner to that of Example 98. 4-(6-Cycloheptylcarbonylaminomethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole IR (Nujol) : 3410, 3320, 1650, 1610 cm NMR (DMSO-dg, δ) : 1.30-1.95 (12H, m), 2.34-2.50 (1H, m), 4.35 (2H, d, J=5.9Hz), 6.93 (4H, s) , 7.06- -7.16 (1H, m) , 7.38 (1H, s), 7.73-7.81 (2H, m), 8.31 (1H, t, J=5.9Hz) Example 91 The following compound was obtained according to a 124 similar manner to that of Example 64. 4-[6-(Amino)(methanesulfonylimino)methylpyridin2-yl1-2-(diaminomethyleneamino) thiazole mp : 265°C (dec.) IR (Nujol) : 3440, 3330, 1630 cm1 NMR (DMSO-dg, δ) : 3.09 (3H, s), 6.94 (4H, s), 8.00-8.10 (2H, m), 8.08 (IH, s), 8.12-8.20 (2H, m), 9.15 (1H, s) Example 92 The following compound was obtained according to a similar manner to that of Example 64. 4-[6-(Amino)(methylaminosulfonylimino)methylpyridin2-yl1-2-(diaminomethyleneamino) thiazole mp : 210-211°C IR (Nujol) ; 3390, 1655, 1590 cm1 NMR (DMSO-dg, δ) ; 2.93 (3H, s), 6.95 (4H, s), 7.82-8.10 (3H, m), 7.87 (IH, s) Example 93 A mixture of 2-(diaminomethyleneamino)-4-[6-(imino)(methoxy)methylpyridin-2-yl]thiazole (4.0 g) and cyanamide (1.2 g) in methanol (80 ml) was stirred for 16 hours at ambient temperature. To the mixture was added a diethyl ether (80 ml) and isolated precipitate was collected by filtration. The precipitate was added to a mixture of ethyl acetate and water and adjusted to pH 9.5 with 20% aqueous potassium carbonate. The precipitate was collected by filtration and recrystallized from a mixture of Ν,Ν-dimethylformamide and ethyl acetate to give 4-[6-(amino)(cyanoimino)methylpyridin-2-y13 -2(diaminomethyleneamino)thiazole (3.04 g). mp : 261°C (dec.) 125 TR (Nujol) : 3380 , 2200, 1640, 1555 cm 1 NMR (DMSO-dg, 5) : 6.96 (4H, s), 8. 00-8.04 : (2H, m) 8.11-8.19 ( 2H , m), 9.06 (IH, s) , 9.40 (IH, s) Anal. Calcd. for C iAoV·1·^0 : C 42.17, H 4.18, N 35.76, H2O 8.62 Found : C 42.23, H 4.16, N 36.00, H2O 8.50 Example 94 To a solution of 4-(6-(amino)(cyanoimino)10 methylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (2.0 g) in a solution of ethanol (60 ml) and chloroform (40 ml) was bubbled with hydrogen chloride for 30 minutes under ice-cooling and the mixture was stirred for 2.5 hours at the same temperature. The solvent was removed by concentration in vacuo. To the residue was added a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 4-[6-(amino)(carbamoylimino)methylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole (1.75 g).

IR (Nujol) : 3430, 1330, 1650 cm1 NMR (DMSO-dg, δ) : 6.42 (IH, s), 6.69 (IH, s), 6.94 (4H, s), 7.93-8.02 (2H, m), 8.06-8.15 (2H, m), 8.64 (IH, s), 9.01 (IH, s) Example 95 A mixture of 2-(diaminomethyleneamino)-4-(630 methoxycarbonylpyridin-2-yl)thiazole (4.0 g) and 100% hydrazine monohydrate (1.05 ml) in ethanol (40 ml) was heated under reflux for 8 hours. To the reaction mixture was added ethyl acetate (60 ml) under stirring at ambient temperature. The isolated precipitate was collected by filtration to give 2-(diaminomethyleneamino)-4-(6126 hydrazinocarbonylpyridin-2-yl)thiazole (3.19 g). mp : 233-234°C IR (Nujol) : 3400, 3300, 1650 (br), 1600 cm-1 NMR (DMSO-dg, δ) : 6.93 (4H, s), 7.79-8.20 (4H, m), .14 (1H, s) Example 96 A mixture of 2-(diaminomethyleneamino)-4-(6hydrazinocarbonylpyridin-2-yl)thiazole (3.0 g) and 2-methyl-2-thiopseudourea sulfate (1.8 g) in dimethylsulfoxide (30 ml) was stirred for 6 hours at 100°C, and then the mixture was cooled to ambient temperature. To the mixture was added ethyl acetate (30 ml) under stirring. The isolated precipitate was collected by filtration and the precipitate was added to a mixture of water and ethyl acetate. The mixture was adjusted to pH 10 with 4N-sodium hydroxide and precipitate was collected by filtration to give 2-(diaminomethyleneamino)-4-(6guanidinocarbamoylpyridin-2-yl)thiazole (2.48 g). mp : 194-196°C IR (Nujol) : 3330 (br), 1600 (br) cm 1 NMR (DMSO-dg + D2O, δ) : 7.64 (1H, s), 7.79-7.98 (3H, m) Example 97 A mixture of 2-(diaminomethyleneamino)-4-(6guanidinocarbamoylpyridin-2-yl)thiazole (2.2 g) in concentrated ammonium hydroxide (22 ml) was heated under reflux for 4 hours and then the mixture was cooled to ambient temperature. To the mixture was added a water (30 ml) and isolated precipitate was collected by filtration to give 4-[6-(5-amino-lH-l,2,4-triazol-3-yl)pyridin-2-yl]2-(diaminomethyleneamino)thiazole (1.34 g). mp : >300°C IR (Nujol) : 3360 (br), 1630 cm-1 - 127 IE 903216 NMR (DMSO-dg, 6) : 5.78 (2H, s), 6.98 (4H, s), 7.71-7.82 (2H, m), 7.90-7.95 (2H, m) Example 98 A mixture of Ν,Ν-dimethylglycine hydrochloride (1.5 g), 1-hydroxybenzotriazole hydrate (1.5 g) and 1-(3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.1 g) in Ν,Ν-dimethylformamide (15 ml) was stirred for 1 hour at ambient temperature. The above mixture was added to a mixture of 4-(6-aminomethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole trihydrochloride (3.0 g) and triethylamine (3.5 ml) in Ν,Ν-dimethylformamide (45 ml) and the mixture was stirred for 2 hours at ambient temperature. The solvent was removed by concentration and the residue was dissolved in a mixture of tetrahydrofuran, ethyl acetate and water. The mixture was adjusted to pH 13.5 with 5N-sodium hydroxide. The separated organic layer was washed with brine and evaporated in vacuo. The residue was triturated with ethyl acetate to give 2-(diaminomethyleneamino)-4-(6-dimethylaminoacetylaminomethylpyridin-2-yl)thiazole (1.96 g). mp : 199°C IR (Nujol) : 3340, 1660, 1600 cm'1 NMR (DMSO-dg, δ) : 2.27 (6H, s), 2.98 (2H, s), 4.44 (2H, d, J=5.9Hz), 6.94 (4H, s), 7.12-7.22 (IH, m), 7.37 (IH, s), 7.79 (2H, d, J=4.5Hz), 8.46 (IH, t, J=5.9Hz) Example 99 The following compound was obtained according to a similar manner to that of Example 18. 2-(Diaminomethyleneamino)-4-(6-dimethylaminoacetylaminomethylpyridin-2-yl) thiazole trihydrochloride. mp : 231-232°C 128 IR (Nujol) : 3270, 3210, 3080, 1680, 1610 cm NMR (D2O, δ) : 3.06 (6H, s), 4.29 (2H, s), 4.95 (2H, s), 7.85 (IH, d, J=7.7Hz), 8.28 (IH, d, J=7.7Hz), 8.28 (IH, s), 5 8.49 (IH, t, J=7.7Hz) Anal. Calcd. for C-.HnQN_OS‘3HC1-H_O : 19 7 2 C 36.49, H 5.25, N 21.28, Cl 23.08, H20 3.91 Found : C 36.22, H 5.10, N 21.05, Cl 23.34, H20 3.83 Example 100 The following compound was obtained according to a similar manner to that of Example 22. 2-(Diaminomethyleneamino)-4-[6-(3-n-propylureido)15 methylpyridin-2-yl)thiazole mp : 215-217°C IR (Nujol) : 3400, 3325, 1620, 1590 cm-1 NMR (DMSO-dg, δ) : 0.85 (3H, t, J=7.4Hz), 1.31-1.49 (2H, m), 2.94-3.08 (2H, m), 20 4.33 (2H, d, J=5.7Hz), 6.20 (IH, t, J=5.7Hz), 6.43 (IH, t, J=5.7Hz), 6.94 (4H, s), 7.14-7.21 (IH, m), 7.46 (IH, s), 7.74-7.83 (2H, m) Example 101 The following compound was obtained according to a similar manner to that of Example 18. 2-(Diaminomethyleneamino)-4-[6-(3-n-propylureido)methylpyridin-2-yl]thiazole dihydrochloride mp : 228-229°C IR (Nujol) : 3360, 3230, 1690, 1610, 1570 cm-1 NMR (DMSO-dg, δ) : 0.86 (3H, t, J=7.4Hz), 1.32· -1.50 (2H, m), 3.02 (2H, t, J=7.0Hz), 4.59 (2H, s), 7.65 (IH, d, J=7.0Hz), 35 8.30 (IH, t, J=7.0Hz), 8.40 (IH, t, J=7.0Hz), 8.55 (5H, s) 129 Anal. Calcd. for C14HigN7OS‘2HCl : C 41.38, H 5.21, N 24.13, Cl 17.45 Found : C 41.36, H 5.12, N 24.22, Cl 17.48 Example 102 The following compound was obtained according to a similar manner to that of Example 17. 2-(Diaminomethyleneamino)-4-(6-methoxycarbonyl10 pyridin-2-yl)thiazole IR (Nujol) : 3440, 3360, 1720, 1650, 1600 cm'1 Example 103 To a mixture of 2-(diaminomethyleneamino)-4-(615 methoxycarbonylpyridin-2-yl)thiazole (0.7 g) and sodium borohydride (0.3 g) in tetrahydrofuran (10 ml) was added a methanol (1.5 ml) at 50-55°C and the mixture was stirred for 1.6 hours at the same temperature. The reaction mixture was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 2-(diaminomethyleneamino)-4(6-hydroxymethylpyridin-2-yl)thiazole (0.57 g). mp : 229°C IR (Nujol) : 3310, 1670, 1600 cm1 NMR (DMSO-dg, δ) : 4.60 (2H, s), 5.43 (1H, s), 6.95 (4H, s), 7.34-7.40 (2H, m), 7.75-7.89 (2H, m) Example 104 A mixture of 2-(diaminomethyleneamino)-4-(6hydroxymethylpyridin-2-yl)thiazole (1.0 g) and thionyl chloride (10 ml) in a mixture of dichloromethane (10 ml) and tetrahydrofuran (10 ml) was stirred for 70 hours at 130 ambient temperature. To the reaction mixture was added a diethyl ether (30 ml) and isolated precipitate was collected by filtration. The precipitate was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 4-(6-chloromethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole (0.97 g). mp : 260-261°C IR (Nujol) : 3380, 1640, 1600 cm1 NMR (DMSO-dg, δ) : 4.79 (2H, s), 6.93 (4H, s), 7.37- 7.48 (IH, m), 7.40 (IH, s), 7.83-7.90 (2H, m) Example 105 A mixture of 4-(6-chloromethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole (1.1 g), 2-mercaptobenzimidazole (0.74 g) and potassium carbonate (0.68 g) in Ν,Ν-dimethylformamide (20 ml) was stirred for 15 hours at ambient temperature. The reaction mixture was added water and extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated to give 4-[6-(benzimidazol-2-yl)25 thiomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (1.22 g). mp ; 209-211°C IR (Nujol) : 3410, 3360, 1650, 1590 cm1 NMR (DMSO-dg, δ) : 4.70 (2H, s), 6.92 (4H, s), 7.10-7.18 (3H, m), 7.30 (IH, s), 7.37- 7.44 (2H, m), 7.75-7.83 (2H, m) Example 106 The following compound was obtained according to a similar manner to that of Example 18. 131 4-[6-(Benzimidazol-2-yl)thiomethylpyridin-2-yl]2-(diaminomethyleneamino)thiazole dihydrochloride. mp : 272°C (dec.) IR (Nujol) : 3320, 1680, 1620 cm1 NMR (DMSO-dg, δ) : 5.04 (2H, s), 7.41-7.56 (4H, m), 7.66-7.75 (2H, m), 7.91 (IH, t, J=7.3Hz), 8.10 (IH, d, J=7.3Hz), 8.39 (4H, s) Anal. Calcd. for C17H15N7S2*2HC1«3/5H2O : C 43.89, H 3.94, N 21.08, Cl 15.24, H2O 2.32 Found: C 43.69, H 4.00, N 20.93, Cl 15.19, H2O 2.28 Example 107 To a solution of 4-(6-cyanomethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole (1.5 g) in chloroform (7.5 ml) and methanol (7.5 ml) was bubbled with hydrogen chloride for 30 minutes under ice-cooling and the mixture was stirred for 3 hours at the same temperature. To the reaction mixture was added diisopropyl ether (15 ml) under stirring and the isolated precipitate was collected by filtration. The precipitate was dissolved in water (50 ml) and stirred for 5 minutes at ambient temperature. The mixture was adjusted to pH 9.5 with potassium carbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated to give 2-(diaminomethyleneamino)-4-(6-methoxycarbonylmethylpyridin-2-yl)thiazole (1.41 g). mp : 208-210°C (dec.) IR (Nujol) : 3410, 1730, 1650, 1590 cm1 NMR (DMSO-dg, δ) : 3.65 (3H, s), 3.88 (2H, s), 6.93 (4H, s), 7.20-7.29 (IH, m), 7.33 (IH, s), 7.71-7.84 (2H, m) Example 108 To a solution of 2-(diaminomethyleneamino)-4-(6132 methoxycarbonyImethylpyridin-2-yl)thiazole (1.3 g) in methanol (30 ml) was bubbled with ammonia for 30 minutes under ice-cooling and the mixture was stirred for 18 hours at ambient temperature. The solvent was removed by concentration in vacuo to give 4-(6-carbamoylmethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.18 g). mp : 254°C IR (Nujol) : 3320, 1620, 1590 cm-1 NMR (DMSO-dg, δ) : 3.61 (2H, s), 6.93 (4H, s), 10 7.02 (1H, S), 7.18-7.25 (1H, m), 7.35 (1H, s), 7.56 (1H, s), 7.73-7.78 (2H, m) Example 109 The following compound was obtained according to a 15 similar manner to that of Example 18. 4-(6-CarbamoyImethylpyridin-2-yl)-2-(diaminomethyleneamino ) thiazole dihydrochloride mp : 250°C (dec.) IR (Nujol) : 3370, 3300, 3120, 1675, 1630, 1600 cm NMR (DMSO-dg, δ) : 4.03 (2H, s), 7.26 (1H, s), 7.64 (1H, d, J=7.8Hz), 7.84 (1H, s), 8.24 (1H, t, J=7.8Hz), 8.36 (1H, d, J=7.8Hz), 8.41 (1H, s), 8.49 (4H, s) Anal. Calcd. for ci1Hi2N6OS*2HCl : C 37.83, H 4.04, N 24.06, Cl 20.30 Found : C 37.58, H 4.03, N 23.87, Cl 20.43 Example 110 The following compound was obtained according to a similar manner to that of Example 17. 4-(6-(2-Acetylaminoethyl)pyridin-2-yl]-2(diaminomethyleneamino) thiazole mp : 220-221°C 133 IR (Nujol) : 3400, 3290, 1630, 1595 cm — X NMR (DMSO-dg, δ) : 1.80 (3H, s), 2.89 (2H, t, J=7.2Hz), 3.40 -3.51 (2H, m), 6.95 (4H, s) 7.09-7.18 (IH, m), 7.39 (IH, s), 7.68-7.76 (2H, m), 7.94 (IH, t, J= 5.4Hz) Example 111 The following compound was obtained according to a similar manner to that of Example 18. — [ '6 — (2 - Acetylaminoethyl) pyr idin- 2 -y 1 ] - 2 (diaminomethyleneamino)thiazole dihydrochloride mp : 272-273°C IR (Nujol) : 3350, 3260, 3690, 1590 cm NMR (DMSO-dg, δ) : 1.78 (3H, s) , 3.07 (2H, t, J=6.8Hz), 3.41-3.55 (2H, m) , 7.24 (IH, d, J=7.5Hz), 8.00-8.10 (2H, m) , 8.15- 8.22 (2H, 8.40 (4H, s) Anal. Calcd. for C13H16NgOS*2HCl : C 41.39, H 4.81, N 22.27, Cl 18.79 Found : C 41.10, H 4.77, N 22.17, Cl 18.58 Example 112 The following compound was obtained according to a similar manner to that of Example 39. 4-[6-(2-Aminoethyl)pyridin-2-yl)-2-(diaminomethyleneamino) thiazole trihydrochloride mp : 159-160°C IR (Nujol) : 3350, 3300, 3220, 1690, 1620, 1595 cm1 NMR (DMSO-dg, δ) : 3.20-3.50 (4H, m), 7.59 (IH, d, 7.8Hz), 8.14 (IH, t, J=7.8Hz), 8.31 (IH, d, J=7.8Hz), 8.38 (4H, s), 8.46-8.60 (3H, m) Anal. Calcd. for C11H14NgS-3HCl-H2O : C 33.90, H 4.91, N 21.56, Cl 27.29, H2O 4.62 Found : C 33.87, H 4.87, N 21.57, Cl 27.07, H2O 4.70 134 Example 113 The following compound was obtained according to a similar manner to that of Example 17. 4-(6-Acetylaminopyridin-2-yl)-2-(diaminomethyleneamino ) thiazole mp : 259°C (dec.) IR (Nujol) : 3440, 3350, 3250, 1660, 1640, 1660 cm1 NMR (DMSO-dg, δ) : 2.12 (3H, s), 6.9? (4H, s), 7.29 (1H, s), 7.61 (1H, dd, J=0.9Hz, and 7.9Hz), 7.79 (1H, t, J=7.9Hz), 7.96 (1H, dd, J=0.9Hz and 7.9Hz), 10.40 (1H, s) Example 114 The following compound was obtained according to a similar manner to that of Example 18. 4-(6-Acetylaminopyridin-2-yl)-2-(diaminomethyleneamino) thiazole dihydrochloride mp: 303 °C IR (Nujol) : 3400, 1680, 1615 cm1 NMR (DMSO-dg, δ) : 2.18 (3H, s), 7.90-8.06 (4H, m), 8.46 (4H, s), 11.02 (1H, s), 12.98 (1H, br s) Anal. Calcd. for C-^H^NgOS·2HC1 ·Η2Ο : C 35.98, H 4.39, N 22.88, Cl 19.31, H2O 4.91 Found : C 35.77, H 4.34, N 22.75, Cl 19.50, H2O 4.80 Example 115 The following compound was obtained according to a similar manner to that of Example 39. 4-(6-Aminopyridin-2-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride mp : 302°C (dec.) IR (Nujol) : 3370, 3280, 1657, 1610 cm1 135 NMR (DMSO-dg, δ) : 6.98 (1H, d, J=8.8Hz), 7.54 (1H, d, J=7.7Hz), 7.96 (1H, dd, J=7.7Hz and 8.8Hz), 8.37 (4H, s), 8.44 (1H, s), 8.73 (2H, s) Anal. Calcd. for C9H1()NgS’2HCl*H2O : C 33.24, H 4.34, N 25.84, Cl 21.80, H2O 5.54 Found : C 33.18, H 4.27, N 26.14, Cl 22.03, H2O 5.79 Example 116 The following compound was obtained according to a 10 similar manner to that of Example 17. 4-(4-Acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino ) thiazole dihydrochloride mp : 222-224°C IR (Nujol) : 3320, 3240, 1690, 1650 cm”1 NMR (DMSO-dg, δ) : 4.54 (2H, d, J=5.9Hz), 7.70 (1H, d, J=6.0Hz), 8.50 (5H, br s), 8.60 (1H, s), 8.72 (1H, d, J=6.0Hz), 8.84 (1H, t, J=5.9Hz) Anal. Calcd. for C12H14NgOS«2HCl«5/4H2O : C 37.36, H 4.83, N 21.78, Cl 18.38 Found : C 37.25, H 4.47, N 21.43, Cl 18.19 Example 117 The following compound was obtained according to a 25 similar manner to that of Example 39. 4-(4-Aminomethylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole trihydrochloride mp : 284-285°C IR (Nujol) : 3300, 1685 cm1 NMR (DMSO-dg, δ) : 4.28 (2H, d, J=5.0Hz), 7.75 (1H, d. J=5.4Hz), 8.28 (1H, s), 8.45 (4H, s) , 8.75 (1H, d, J=5.4Hz), 8.76 (1H, s) , 9.02 (3H, br s) - 136 IE 903216 Example 118 4-(4-Aminomethylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole (1.09 g) was dissolved in water (10 ml) and the solution was adjusted to pH 4 with aqueous sodium hydrogen carbonate. Potassium cyanate (0.25 g) was added to the solution and the mixture was stirred for one hour at ambient temperature. After the pH was readjusted to 4 with 6N-hydrochloric acid, additional potassium cyanate (0.25 g) was added and the mixture was further stirred for 6 hours. The reaction mixture was made basic with aqueous potassium carbonate and the resulting precipitate was collected by filtration. The crude product was chromatographed on silica gel with use of chloroform-methanol (8:2) as eluent and converted to the dihydrochloride in a usual manner. This salt was recrystallized from an aqueous ethanol to give 2-(diaminomethyleneamino)-4-(4-ureidomethylpyridin-2-yl)thiazole dihydrochloride (0.70 g). mp : 213-214°C IR (Nujol) : 3450, 3330, 3275, 3175, 3075, 1685 cm'1 NMR (DMSO-dg, δ) : 4.45 (2H, s), 7.00 (IH, br s), 7.67 (IH, d, J=5.8Hz), 8.47 (5H, s), 8.53 (IH, s), 8.72 (1H, d, J=5.8Hz) Anal. Calcd. for C11H13N7OS«2HC1«H2O : C 34.56, H 4.48, N 25.64, Cl 18.55, H2O 4.71 Found: C 34.62, H 4.40, N 25.35, Cl 18.76, H2O 4.95 Example 119 The following compound was obtained according to a similar manner to that of Example 17. 4-(4-Cyanopyridin-2-yl)-2-(diaminomethyleneamino)thiazole hydrobromide mp : >300°C IR (Nujol) : 3440, 3325, 3190, 3070, 2240, 1690 cm 137 NMR (DMSO-dg, δ) : 7.84 (IH, dd, J=1.5Hz and 5.0Hz), 8.09 (IH, s), 8.24 (4H, s), 8.67 (IH, d, J=1.5Hz), 8.85 (IH, d, J=5.0Hz) Anal. Calcd. for C^gHgNgS«HBr : C 36.94, H 2.79, N 25.84, Br 24.57 Found : C 37.13, H 2.72, N 25.61, Br 24.19 Example 120 The following compound was obtained according to a 10 similar manner to that of Example 63. 2-(Diaminomethyleneamino)-4-[4-(imino)(methoxy)methylpyridin-2-yl]thiazole mp : 214-215°C IR (Nujol) : 3450, 3270, 3110, 1650 cm1 NMR (DMSO-dg, δ) : 3.85 (3H, s), 6.92 (4H, br s), 7.47 (IH, s), 7.61 (IH, d, J=5.0Hz), 8.23 (IH, s), 8.60 (IH, d, J=5.0Hz), 9.59 (IH, s) Example 121 The following compound was obtained according to a similar manner to that of Example 64. 4-(4-( Amino)(aminosulfonylimino)methylpyridin-2-yl]25 2-(diaminomethyleneamino) thiazole mp : 234-235°C IR (Nujol) : 3440, 3330, 1665, 1335, 1145, 1070 cm1 NMR (DMSO-dg, δ) : 6.87 (2H, s), 6.96 (4H, s), 7.50 (IH, s), 7.64 (IH, dd, J=1.6Hz and 5.1Hz), 30 7.78 (IH, s), 8.24 (IH, d, J=1.6Hz), 8.70 (IH, d, J=5.1Hz), 9.03 (IH, s) Anal. Calcd. for cioHi2N8°2S2 : C 35.29, H 3.55, N 32.92 Found : C 35.68, H 3.49, N 32.54 138 Example 122 1N-Aqueous sodium hydroxide (10 ml) was added to a suspension of 4-(4-cyanopyridin-2-yl)-2-(diaminomethyleneamino) thiazole hydrobromide (1.00 g) in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml). After the mixture was stirred for one day at ambient temperature, the solvent was evaporated in vacuo and the residue was mixed with water (10 ml). The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of Ν,Ν-dimethylformamide and water to give 4-(4-carbamoylpyridin-2-yl)-2-(diaminomethyleneamino) thiazole (0.45 g). mp : 169-171°C IR (Nujol) : 3450, 3330, 3175, 1665 cm-1 NMR (DMSO-dg, δ) : 6.97 (4H, br s), 7.48 (IH, s), 7.66 (IH, dd, J=1.6Hz and 5.0Hz), 7.77 (IH, s), 8.22 (IH, d, J=1.6Hz), 8.40 (IH, s), 8.69 (IH, d, J=5.0Hz) Anal. Calcd. for ειοΗ10Ν60δ’Η2° : C 42.85, H 4.31, N 29.98, H20 6.43 Found : C 43.05, H 4.23, N 29.72, H2O 6.64 Example 123 The following compound was obtained according to a 25 similar manner to that of Example 17. 2-(Diaminomethyleneamino)-4-(2-ethoxycarbonylpyridin4-yl)thiazole mp : 234-236°C IR (Nujol) : 3375, 1715 cm 1 NMR (DMSO-dg, δ) : 1.36 (3H, t, J=7.1Hz), 4.38 (2H, g, J=7.1Hz), 6.99 (4H, br s), 7.73 (IH, s), 8.04 (IH, dd, J=1.7Hz and 5.1Hz), 8.38 (IH, d, J=1.7Hz), 8.69 (IH, d, J=5.1Hz) 139 Example 124 The following compound was obtained according to a similar manner to that of Example 103. 2-(Diaminomethyleneamino)-4-(2-hydroxymethylpyridin4-yl)thiazole mp : 260-261°C IR (Nujol) : 3400, 3100, 1650 cm1 NMR (DMSO-dg, δ) : 4.58 (2H, d, J=5.7Hz), 5.43 (1H, t, J=5.7Hz), 6.67 (4H, br s), 7.51 (1H, s), 7.64 (1H, dd, J=1.5Hz and 5.2Hz), 7.84 (1H, d, J=1.5Hz), 8.46 (1H, d, J=5.2Hz) Example 125 The following compound was obtained according to a similar manner to that of Example 104. 4-(2-Chloromethylpyridin-4-yl)-2-(diaminomethyleneamino) thiazole mp : >93°C IR (Nujol) : 1630 cm 1 NMR (DMSO-dg, δ) : 4.79 (2H, s), 6.97 (4H, br s), 7.58 (1H, s), 7.76 (1H, dd, J=1.6Hz and 5.2Hz), 7.96 (1H, d, J=1.6Hz), 8.54 (1H, d, J=5.2Hz) Example 126 Potassium phthalimide (1.65 g) was added to a solution of 4-(2-chloromethylpyridin-4-yl)-2-(diaminomethyleneamino) thiazole (2.39 g) in Ν,Ν-dimethylformamide 30 (25 ml). After stirring for 14 hours, the solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and washed with ethanol and then diisopropyl ether to give 2-(diaminomethyleneamino)-4-(2-phthalimidomethylpyridin4-yl)thiazole (2.68 g). - 140 IE 903216 mp : 280-281°C IR (Nujol) : 3425, 1700, 1650 cm-1 NMR (DMSO-dg, δ) : 4.96 (2H, s), 6.95 (4H, br s), 7.56 (1H, s), 7.68 (1H, d, J=5.1Hz), 7.85 (1H, s), 7.88-7.96 (4H, m), 8.39 (1H, d, J=5.1Hz) Example 127 A mixture of 2-(diaminomethyleneamino)-4-(210 phthalimidomethylpyridin-4-yl)thiazole (1.57 g) and hydrazine hydrate (0.63 g) in ethanol (25 ml) was refluxed for two hours. The resulting precipitate was filtered off and washed with methanol (20 ml). The two organic layer was combined and evaporated in vacuo to give 4-(2-aminomethylpyridin-4-yl)-2-(diaminomethyleneamino)thiazole (1.00 g). mp : >210°C IR (Nujol) : 3300, 3100, 1610 cm-1 NMR (DMSO-dg, δ) : 3.86 (2H, s), 6.99 (4H, br s), 7.50 (1H, s), 7.65 (1H, dd, J=1.5Hz and 5.1Hz), 7.83 (1H, d, J=1.5Hz), 8.47 (1H, d, J=5.1Hz) Example 128 The following compound was obtained according to a 25 similar manner to that of Example 2. 4-(2-Acetylaminomethylpyridin-4-yl)-2-(diaminomethyleneamino ) thiazole dihydrochloride mp : 246-248°C IR (Nujol) : 3340, 3250, 1665, 1620 cm’1 NMR (DMSO-dg, δ) : 1.97 (3H, s), 4.63 (2H, d, J=5.6Hz), 8.39-8.43 (6H, m), 8.57 (1H, s), 8.78 (1H, d, J=6.0Hz), 8.86 (1H, t, J=5.6Hz) Anal. Calcd. for ci2H14N6OS’2HCl‘H2° : C 37.80, H 4.76, N 22.04, Cl 18.60, H2O 4.72 Found : C 37.86, H 4.80, N 22.10, Cl 18.62, H2O 5.01 141 Example 129 The following compound was prepared according to a similar manner to that of Example 126. 4-(4-Chloro-6-phthalimidomethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole mp : 258-259°C IR (Nujol) : 3450, 3410, 1765, 1700, 1650 cm1 NMR (DMSO-dg, δ) : 4.94 (2H, s), 6.87 (4H, hr s), 7.01 (IH, s), 7.48 (IH, d, J=1.7Hz), 7.86 (IH, d, J=1.7Hz), 7.89-7.98 (4H, m) Example 130 The following compound was obtained according to a 15 similar manner to that of Example 104. 4-{4-Chloro-6-chloromethylpyridin-2-yl)-2(diaminomethyleneamino) thiazole mp : >300°C IR (Nujol) : 3430, 1645 cm 1 NMR (DMSO-dg, δ) : 4.80 (2H, s), 6.91 (4H, br s), 7.49 (IH, s), 7.57 (IH, d, J=1.8Hz), 7.97 (IH, d, J=1.8Hz) Example 131 The following compound was obtained according to a similar manner to that of Example 103. 4-(4-Chloro-6-hydroxymethylpyridin-2-yl)-230 (diaminomethyleneamino)thiazole mp : 243-244°C IR (Nujol) : 3475, 3325, 1665 cm1 NMR (DMSO-dg, δ) : 4.59 (2H, d, J=5.7Hz), .57 (IH, t, J=5.7Hz), 6.90 (4H, br s), 7.40 (IH, d, J=1.9Hz), 7.45 (IH, s), 142 7.84 (1H, d, J=1.9Hz) Example 132 The following compound was obtained according to a 5 similar manner to that of Example 17. 4-(4-Chloro-6-methoxycarbonylpyr idin-2-y1)-2(diaminomethyleneamino) thiazole mp : 258-259°C IR (Nujol) : 3300, 3070, 1715, 1675 cm1 NMR (DMSO-dg, δ) : 3.94 (3H, s), 8.00 (IH, d, J=1.9Hz), 8.02 (IH, s), 8.33 (4H, s), 8.58 (IH, d, J=1.9Hz) « Example 133 Ammonia gas was bubbled to a suspension of 4-(2-acetoxyacetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino) thiazole (200 mg) in methanol (20 ml) for 30 minutes with cooling on an ice-water bath. The solvent was removed by filtration. Recrystallization from a mixture of water and methanol afforded 2-(diaminomethyleneamino)-4-(2-hydroxyacetylaminomethylthiazol-4-yl)thiazole (180 mg). mp : 239°C IR (Nujol) : 3450, 3340, 1630 cm-1 NMR (DMSO- dg, δ) : 3.91 (2H, d, J=5. 8Hz) , 4.59 (2H, d, J=6.2Hz), 5.63 (IH, t, J= =5.8Hz), 6.89 (4H, s), 7.01 (IH, s), 7.78 (IH, s) , 8.68 (IH, t, J=6.2Hz) Anal. Calcd. for c-i qh-i 2N6°2S2 : C 38.45, H 3.87, , N 2 6.90 Found : C 38.43, H 3.84, N 27.06 Example 134 A suspension of 4-(2-aminomethylthiazol-4-yl)-2- 143 IE 903216 (diaminomethyleneamino)thiazole (1.0 g), acetoxyacetyl chloride (0.45 g) and triethylamine (0.93 g) in methylenechloride (30 ml) was stirred with cooling on an ice-water bath for 8 hours. The solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was neutralized with a saturated aqueous sodium bicarbonate solution and then was extracted with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (60 ml). The extract was dried with magnesium sulfate and then was evaporated. The residue was chromatographed on a silica gel column eluting with chloroformxmethanol = 10:1. Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-(diaminomethyleneamino)-4(2-acetoxyacetylaminomethylthiazol-4-yl)thiazole (0.2 g). mp : 182-183°C IR (Nujol) : 3430, 3280, 1745, 1675, 1600 cm'1 NMR (DMSO-dg, δ) : 2.11 (3H, s), 4.55 (2H, s), 4.59 (2H, d, J=6.1Hz), 6.89 (4H, s), 7.02 (1H, s), 7.81 (1H, s), 8.95 (1H, t, J=6.lHz) Anal. Calcd. for ci2H14N6°3S2 : C 40.67, H 3.98, N 23.71 Found : C 40.56, H 4.00, N 23.99 Example 135 The following compound was obtained from 4-bromoacetyl-2-(diaminomethyleneamino)thiazole according to a similar manner to that of the latter of Example 9. 4-( 2-Cyanomethyl thiazol-4-yl )-*-2- (diaminomethyleneamino ) thiazole IR (Nujol) : 3400, 2200, 1650, 1600 cm'1 NMR (DMSO-dg, δ) : 7.92 (1H, s), 7.07 (1H, s), 6.90 (4H, s), 4.60 (2H, s) 144 Example 136 The following compound was obtained according to a similar manner to that of Example 36. 2-(Diaminomethyleneamino)-4-[2-(2-methanesulfonyl-3methylguanidino)methylthiazol-4-yl]thiazole mp : 229-231°C (dec.) IR (Nujol) : 3420, 3350, 1600, 1625 cm-1 NMR (DMSO-dg, δ) : 2.78 (6H, br), 4.66 (2H, d, J=5.7Hz), 6.89 (4H, s), 7.02 (IH, s), 7.21 (IH, g, J=4.8Hz), 7.81 (IH, s), 7.85 (IH, d, J=5.7Hz) Example 137 4-(6-Acetylaminomethyl-4-chloropyridin-2-yl)-215 (diaminomethyleneamino)thiazole (160 mg) was hydrogenated over 10% palladium on carbon (50% wt) (50 mg) in methanol (5 ml) at atmospheric pressure of hydrogen for 8 hours at ambient temperature. After the catalyst was removed by filtration, the solvent was evaporated in vacuo and the residue was mixed with water. The solution was adjusted to pH 10 with aqueous potassium carbonate and the free base was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin25 2-yl)-2-(diaminomethyleneamino)thiazole (0.13 g).

IR (Nujol) : 1655, 1590, 1545 cm1 Example 138 The following compound was obtained according to a similar manner to that of Example 43. 2-(Diaminomethyleneamino)-4-(6-isobutyrylaminomethylpyridin-2-yl) thiazole NMR (DMSO-dg, δ) : 1.07 (6H, d, J=6.8Hz), 2.43-2.57 (IH, m), 4.36 (2H, d, J=5.9Hz), 145 6.92 (4H, br s), 7.09-7.14 (1H, m) , 7.39 (1H, s), 7.77-7.80 (1H, m), 8.36 (1H, t, J=5.9Hz) Example 139 The following compound was obtained according to a similar manner to that of Example 43. 2-(Diaminomethyleneamino)-4-(6-pivaloylaminomethy1pyridin-2-yl) thiazole NMR (DMSO-dg, δ) : 1.18 (9H, s), 4.38 (2H, d, J=5.9Hz), 6.92 (4H, br s), 7.07 (1H, dd, J=5.5Hz and 5.6Hz), 7.36 (1H, s), 7.76-7.83 (1H, m) , 8.16 (1H, t, J=5.9Hz) Example 140 The following compound was obtained according to a similar manner to that of Example 43. 2-(Diaminomethyleneamino)-4-(6-methoxycarbonyl20 methoxyacetylaminomethylpyridin-2-yl) thiazole mp : 200-201°C IR (Nujol) : 3420, 3175, 1755, 1670 cm-1 NMR (DMSO-dg, δ) : 3.67 (3H, s), 4.10 (2H, s), 4.30 (2H, s) , 4.45 (2H, d, J=5.8Hz), 25 6.92 (4H, br s), 7.20 (1H, t, J=4.0Hz), 7.79 (2H, a, J=4.0Hz), 8.47 (1H, t, J=5.8Hz) Example 141 The following compound was obtained according to a 30 similar manner to that of Example 43. 2-(Diaminomethyleneamino)-4-(6-ethoxycarbonylaminomethy lpyridin-2-yl)thiazole NMR (DMSO-dg, δ) : 1.19 (3H, t, J=7.1Hz), 4.04 (2H, q, J=7.lHz), 4.30 (2H, d, J=6.2Hz), 146 6.92 (4H, br s), 7.16 (IH, dd, J=5.7Hz and 5.8Hz), 7.38 (IH, s), 7.71 (IH, t, J=6.2Hz), 7.79 (IH, d, J=5.8Hz), 7.80 (IH, d, J=5.7Hz) Example 142 The following compound was obtained according to a similar manner to that of Example 43. 2-(Diaminomethyleneamino)-4-(6-isobutoxycarbonyl10 aminomethylpyridin-2-yl)thiazole hemi-fumarate mp : 255-257°C IR (Nujol) : 3320, 1705, 1690 cm'1 NMR (DMSO-dg, δ) : 0.90 (6H, d, J=6.7Hz), 1.87 (IH, sept., J=6.7Hz), 3.78 (2H, d, J=6.7Hz), 4.30 (2H, d, J=6.2Hz), 6.62 (IH, s), 7.03 (4H, br s), 7.17 (IH, dd, J=3.3Hz and 5.5Hz), 7.40 (IH, s), 7.73-7.81 (3H, m) Example 143 The following compound was obtained according to a similar manner to that of Example 63. 2-(Diaminomethyleneamino)-4-(6-(3-imino-3methoxypropyl)pyridin-2-yl]thiazole mp : 180-182°C IR (Nujol) : 3370, 3290, 1650, 1590 cm-1 NMR (DMSO-dg, δ) : 3.56 (3H, s), 6.93 (4H, s), 7.10-7.23 (IH, m), 7.39 (IH, s), 7.67-7.76 (2H, m), 8.01 (IH, br s) Example 144 The following compound was obtained according to a similar manner to that of Example 64. 4-(6-(3-Amino-3- (aminosulfonylimino)propyl]pyridin-2 - 147 IE 903216 yl ]-2- (diaminomethyleneamino)thiazole IR (Nujol) : 3450, 3340, 1630, 1605cm NMR (DMSO-d,, 6) : 2.60-2.69 (2H, m), 2.99-3.08 (2H, m), 6.50 (2H, s) , 6.93 (4H, s), 5 7.14-7.25 (IH, m), 7.36 (IH, s) , 7.43 (IH, s), 7.71-7.75 (2H, m), 8.32 (IH, s) Example 145 The following compound was obtained according to a 10 similar manner to that of Example 17. 4-(2-Carbamoylpyridin-4-yl)-2-(diaminomethyleneamino ) thiazole mp : 276 to 277°C IR (Nujol) : 3410, 1675 cm-1 NMR (DMSO-dg, δ) : 6.98 (4H, br s), 7.70 (2H, s), 7.98 (IH, dd, J=1.7Hz and 5.1Hz), 8.13 (IH, s) 8.36 (IH, d, J=1.7Hz), 8.61 (IH, d, J=5.lHz) Example 146 The following compound was obtained according to a similar manner to that of Example 17. 2-(Diaminomethyleneamino)-4-(5-methoxycarbonyl25 pyridin-3-yl)thiazole mp : 248-249°C (dec.) IR (Nujol) : 3320, 3050, 1720, 1610 cm1 NMR (DMSO-dg, δ) : 3.92 (3H, s), 7.00 (4H, s), 7.55 (IH, s), 8.58 (IH, t, J=2.1Hz), 8.97 (IH, d, J=2.1Hz), 9.31 (IH, d, J=2.1Hz) Anal. Calcd. for chh;l1N5O2S : C 47.64, H 4.00, N 25.26 Found : C 47.35, H 3.90, N 25.00 - 148 IE 903216 Example 147 A suspension of 2-(diaminomethyleneamino)-4-(5methoxycarbonylpyridin-3-yl)thiazole (500 mg) in 28% ammonia solution (15 ml) and tetrahydrofuran (15 ml) was stirred at room temperature for 9.5 hours. The solvent was removed under reduced pressure. The residue was washed with methanol to afford 4-(5-carbamoylpyridin-3yl)-2-(diaminomethyleneamino)thiazole (350 mg). mp : 262-263° C (dec IR (Nujol) : 3430, 3310, 3190, 1680, 1630, 1600 cm NMR (DMSO-dg, δ) : 6.93 (4H, s) , 7.43 (1H, s), 7.65 (1H, s), 8.25 ( 1H, s), 8.55 (1H, t, J=2.1Hz), 8.90 (1H, d, J= 2.1Hz), 9.18 (1H, d, J=2.lHz) Example 148 A solution of sodium borohydride (1.2 g) in water (25 ml) was added slowly to a solution of 2-(diaminomethyleneamino)-4-(5-methoxycarbonylpyridin-3yl)thiazole (2.8 g) in methanol (70 ml) and tetrahydrofuran (70 ml) under refluxing for 20 minutes.

The mixture was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (100 ml). The mixture was extracted with a mixture of ethyl acetate (300 ml) and tetrahydrofuran (150 ml). The extract was dried with magnesium acetate and then evaporated to afford 2-(diaminomethyleneamino)-4-(5-hydroxymethylpyridin-3-yl)thiazole (1.14 g). mp : 204-205°C (dec) IR (Nujol) : 3300, 1650, 1605 cm1 DMSO· -dg, δ) : 4.57 (2H, d, J=5.6Hz), 5.36 (1H, t, J=5.6Hz), 6.94 (4H, s), 7.33 (1H, s) , 8.10 (1H, br) z 8.92 (1H, d, J=1.9Hz), 8.94 (1H, d, J=2.1Hz) - 149 IE 903216 Example 149 The following compound was obtained according to a similar manner to that of Example 104. 4-(5-Chloromethylpyridin-3-yl)-2-(diaminomethyleneamino ) thiazole mp : 208-210°C (dec.) IR (Nujol) : 3470, 3300, 1630 cm-1 NMR (DMSO-dg, δ) : 4.86 (2H, s), 6.93 (4H, s), 7.40 (IH, s), 8.27 (IH, t, J=2.lHz), 8.54 (IH, d, J=2.1Hz), 9.04 (IH, d, J=2.lHz) Example 150 The following compound was obtained according to a 15 similar manner to that of Example 126. 2-(Diaminomethyleneamino)-4-(5-phthalimidomethylpyridin-3-yl) thiazole mp : 237-239°C IR (Nujol) : 3450, 3310, 1670, 1610 cm1 NMR (DMSO-dg, δ) : 4.86 (2H, s), 6.92 (4H, s), 7.35 (IH, s) , 7.96-7.83 (4H, m), 8.12 (IH, t. J=2.0Hz), 8.44 (IH, d, J=2.0Hz), 8.97 (IH, d, J=2.0Hz) Example 151 A suspension of 2-(diaminomethyleneamino)-4-(5phthalimidomethylpyridin-3-yl)thiazole (2.47 g) and hydrazine hydrate (0.4 g) in methanol was stirred at room temperature for 5 hours. 3N hydrochloride solution (40 ml) was added slowly and then the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml) and then the resulting precipitate was removed by filtration. The solvent was removed under 150 reduced pressure to afford 4-(5-aminomethylpyridin-3-yl)2- (diaminomethyleneamino) thiazole trihydrochloride.

NMR (DMSO-dg, δ) : 4.31 (2H, q, J=5.2Hz), 8.27 (1H, s), 8.44 (4H, s), 8.99 (1H, br), 9.08 (2H, br), 9.52 (1H, br), 9.50 (1H, br) This compound was dissolved in water (30 ml) and then the mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The mixture was extracted with a mixture of ethyl acetate (150 ml) and tetrahydrofuran (75 ml). The extract was dried with magnesium sulfate and then evaporated to afford 4-(5-aminomethylpyridine-3-y1)-2-(diaminomethyleneamino)thiazole (1.07 g).

NMR (DMSO-dg, δ) : 3.77 (2H, br), 6.87 (2H, br), 6.92 (4H, s), 7.30 (1H, s), 8.13 (1H, t, J=2.1Hz), 8.41 (1H, d, J=2.1Hz), 8.90 (1H, d, J=2.1Hz) Example 152 The following compound was obtained according to a similar manner to that of Example 58. 4- (5-Cyanopyridin-3-yl)-2-(diaminomethyleneamino)25 thiazole mp : 224-225°C (dec.) IR (Nujol) : 3400, 2225, 1660, 1610 cm'1 NMR (DMSO-dg, δ) : 6.89 (4H, s), 7.57 (1H, s), 8.75 (1H, dd, J=1.9Hz and 2.1Hz), 8.89 (1H, d, J=1.9Hz), 9.35 (1H, d, J=2.2Hz), 9.35 (1H, d, J=2.2Hz) Example 153 The following compound was obtained according to a similar manner to that of the former of Example 2. 151 2-(Diaminomethyleneamino)-4-(5-acetylaminomethylpyridin-3-yl) thiazole IR (Film) : 3330, 1630 cm1 NMR (DMSO-dg, δ) : 8.94 (IH, d, J=2.1Hz), 8.42 (IH, t, J=5.8Hz), 8.37 (IH, d, J=2.lHz), 8.04 (IH, t, J=2.1Hz), 7.32 (IH, s), 6.93 (4H, s), 4.32 (2H, d, J=5.8Hz), 1.89 (3H, s) Example 154 A mixture of 4-(4-chloro-6-phthalimidomethylpyridin2-yl)-2-(diaminomethyleneamino)thiazole (1.10 g) and hydrazine mono-hydrate (400mg) in ethanol (200 ml) was refluxed for 5 hours. After the solvent and excess hydrazine monohydrate were removed by concentration, water (10 ml) was added to the residue and the suspension was adjusted to pH 2 with 6N-hydrochloric acid. The resulting precipitate was filtered off, washed with water (5 ml) and the filtrate and the washing solution were combined.

After the solution was readjusted to pH 4 with aqueous sodium bicarbonate, potassium cyanate (320 mg) was added to the solution and the mixture was stirred for 14 hours at ambient temperature. The reaction mixture was readjusted to pH 4 with 6N-hydrochloric acid, additional potassium cyanate (215 mg) was added and the solution was further stirred for 8 hours. The mixture was made basic to pH 10 with aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of Ν,Ν-dimethylformamide and water to give 4-(4-chloro-6-ureidomethylpyridin-2-yl)30 2-(diaminomethyleneamino)thiazole (0.28 g). mp : >300°C IR (Nujol) : 3410, 3220, 1660, 1640 cm1 NMR (DMSO-dg, δ) : 4.29 (2H, d, J=5.9Hz), .74 (2H, s), 6.62 (IH, t, J=5.9Hz), 7.07 (4H, br s), 7.23 (IH, d, J=1.8Hz), 152 7.58 (IH, s), 7.87 (IH, d, J=1.8Hz) Anal. Calcd. for C^^H^2N7C1OS· 1/21^0 : C 39.46, H 3.91, N 29.29, H2O 2.69 Found : C 39.72, H 3.82 , N 29.13, H20 2.69 Example 155 The following compound was obtained according to a similar manner to that of Example 154. 4-(6-Acetylaminomethyl-4-chloropyridin-2-yl)-2(diaminomethyleneamino) thiazole mp : 251-252°C IR (Nujol) : 3350, 3100, 1660, 1635 cm-1 NMR (DMSO-dg, δ) : 1.94 (3H, s), 4.36 (2H, d, J=5.9Hz), 6.89 (4H, br s), 7.23 (IH, d, J=1.9Hz), 7.49 (IH, s), 7.85 (IH, d, J=1.9Hz), 8.48 (IH, t, J=5.9Hz) Anal. Calcd. for C^H^ClNgOS : C 44.38, H 4.03, N 25.87 Found : C 44.53, H 4.07, N 25.55

Claims (21)

1. A compound of the formula : R 2 NH \ 3 / R NH -Y-A-R 1 wherein R 1 is amino which may have suitable substituent(s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : in which R is hydrogen, cyano or acyl, and R is amino or lower alkoxy, 2. 3 R and R are each hydrogen, acyl or lower alkyl which may have halogen; or 2 3 R and R are linked together to form lower alkylene, hydrogen or halogen, and A is bond or lower alkylene, provided that when R 1 is amino which may have suitable substituent(s) and A is bond; or R 1 is lower alkylthioureido 154 ,O, .’'j ,.-:1 /.¾ „ ‘ ?,'<./ . RlWI - f ’· * ’-•'I· and A is lower alkylene, then ,6 Y is IN and pharmaceutically acceptable salt thereof.

2. A compound of the formula : r 2 nh

3. / R NH N-r=N—ί o J -Y-A-R wherein R x is amino which may have suitable substituent!s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : N-R 4 11 5 -C-R in which R is hydrogen, cyano or acyl, and R is amino or lower alkoxy, 2 3 R and R are each hydrogen, acyl or lower alkyl which may have halogen; or 2 3 R and R are linked together to form lower alkylene, Y is IN , in which R is hydrogen or halogen, and A is bond or lower alkylene, and pharmaceutically acceptable salt thereof. A compound of the formula : 155 R 2 NH N-—Y-A-R J r 3 nh wherein R is amino which may have suitable substituent(s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : N-R -C-R' in which R is hydrogen, cyano or acyl, and R is amino or lower alkoxy, 2 3 R and R are each hydrogen, acyl or lower alkyl which may have halogen; or 2 3 R and R are linked together to form lower alkylene, S A is bond or lower alkylene, provided that when R 1 is amino which may have suitable substituent (s) excluding lower alkylthioureido, then A is lower alkylene, and pharmaceutically acceptable salts thereof.

4. A compound of claim 2, wherein R 1 is amino, mono or di(lower)alkylamino, acylamino, eyelo(lower)alkynylamino having amino and oxo, imido optionally benzene-fused 5- or 630 156 heteromonocyclic amino which may be substituted by one or more substituent!s) selected from the group consisting of lower alkyl, amino and oxo, 2-cyano-3-lower alkylguanidino, 2-acyl-3-lower alkylguanidino, 2-acylguanidino, (1-lower alkylamino-2-nitrovinyl)amino, hydroxy, halogen, cyano, acyl, unsaturated condensed heterocyclic thio containing 1 to 3 nitrogen atom(s), 5- or 6-membered heteromonocyclic group, or a group of the formula : in which R is hydrogen, cyano, or acyl, and R is amino or lower alkoxy.

5. A compound of claim 4, wherein R 1 is amino, mono or di(lower)alkylaminoureido, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylsulfonylamino, lower alkoxy(lower)alkanoylamino, mono or di or trihalo(lower)alkanoylamino, hydroxy(lower)alkanoylamino, protected hydroxy(lower)alkanoylamino, amino(lower)alkanoylamino, protected amino(lower)alkanoylamino, lower alkoxycarbonyl(lower) alkoxy(lower)alkanoylamino, lower alkylthio(lower)alkanoylamino, lower alkanoyl!lower)alkanoylamino, mono or di (lower)alkylamino(lower)alkanoylamino, furyl(lower)alkylthio(lower)alkanoylamino, lower alkylureido, lower alkylthioureido, 157 cyclo(lower)alkanecarbonylamino, lower alkylcyclo(lower)alkanecarbonylamino, furoylamino, nicotinoylamino, cyclo(lower)alkenylamino having amino and oxo, imido, triazolylamino substituted by amino, triazolylamino substituted by amino and lower alkyl, benzoisothiazolylamino substituted by oxo, 2-cyano-3-lower alkylguanidino, 2-lower alkanesulfonyl-3-lower alkylguanidino, 2-lower alkanesulfonylguanidino, (1-lower alkylamino-2-nitrovinyl)amino, hydroxy, halogen, cyano, carbamoyl, aminocarbamoyl, guanidinocarbamoyl, lower alkoxycarbonyl, lower alkanoyl, benzimidazolylthio, triazolyl substituted with amino or a group of the formula : N-R -C-R' in which R is hydrogen, cyano, carbamoyl, sulfamoyl, lower alkylsulfonyl and mono or di (lower)alkylsulfamoyl, and R 5 is amino or lower alkoxy, R is hydrogen, lower alkylcarbamoyl or mono or di or trihalo(lower) alkyl, R is hydrogen, or 2 3 R and R are linked together to form lower alkylene. A compound of claim 4, wherein R 1 is lower alkanoylamino or ureido, 2 3 R and R are each hydrogen, is t and 156 A is lower alkylene.

6. 7. A compound of claim 6, which is selected from the group consisting of 4-(6-acetylaminomethylpyridin-2-yl)-2(diaminomethyleneamino)thiazole or its mono- or dihydrochloride, and 2-(2-diaminomethyleneamino)-4-(6ureidomethylpyridin-2-yl)thiazole or its mono- or dihydrochloride.

7. 8. A compound of claim 3, wherein R 1 is amino, mono or di(lower)alkylamino, acylamino excluding lower alkylthioureido, cyclo(lower)alkenylamino having amino and oxo, imido optionally benzene-fused 5- or 6heteromonocyclic amino which may be substituted by one or more substituent(s) selected from the group consisting of lower alkyl, amino and oxo, 2-cyano-3-lower alkylguanidino, 2-acyl-3-lower alkylguanidino, 2-acylguanidino, (1-lower alkylamino-2-nitrovinyl)amino, hydroxy, halogen, cyano, acyl, unsaturated condensed heterocyclic thio containing 1 to 3 nitrogen atom(s), 5- or 6 membered heteromonocyclic group, or a group of the formula : in which R is hydrogen, cyano, or acyl, and R is amino or lower alkoxy, provided that when R 1 is acylamino excluding lower alkylthioureido, then A is lower alkylene. 15 9

8. 9. A compound of claim 8, wherein R 1 is amino, mono or di(lower)alkylaminoureido, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylsulfonylamino, lower 5 alkoxy(lower)alkanoylamino, mono or di or trihalo(lower)alkanoylamino, hydroxy(lower)alkanoylamino, protected hydroxy(lower)alkanoylamino, amino(lower)alkanoylamino, protected

9. 10 amino(lower)alkanoylamino, lower alkoxycarbonyl(lower) alkoxy(lower)alkanoylamino, lower alkylthio(lower)alkanoylamino, lower alkanoyl(lower)alkanoylamino, mono or di (lower)alkylamino(lower)alkanoylamino, 15 fury1(lower)alkylthio(lower)alkanoylamino, lower alkylureido, cyclo(lower)alkanecarbonylamino, lower alkylcyclo(lower)alkanecarbonylamino, furoylamino, nicotinoylamino, cyclo(lower)alkenylamino having amino and oxo, 20 imido, triazolylamino substituted by amino, triazolylamino substituted by amino and lower alkyl, benzoisothiazolylamino substituted by oxo, 2-cyano-3-lower alkylguanidino, 2-lower alkanesulfonyl-3-lower alkylguanidino, 2-lower 25 alkanesulfonylguanidino, (1-lower alkylamino-2-nitrovinyl)amino, hydroxy, halogen, cyano, carbamoyl, aminocarbamoyl, guanidinocarbamoyl, lower alkoxycarbonyl, lower alkanoyl, benzimidazolylthio, triazolyl 30 substituted with amino of a group of the formula : N-R -C-R 16 0 d in which R is hydrogen, cyano, carbamoyl, sulfamoyl, lower alkylsulfonyl and mono or di (lower)alkylsulfamoyl, and 5 R is ammo or lower alkoxy, R is hydrogen, lower alkylcarbamoyl or mono or di or trihalo(lower) alkyl, 3 . R is hydrogen, or 2 3 R and R are linked together to form lower alkylene, and A is lower alkylene. A compound of R 1 is ureido, 2 3 R and R are claim 9, wherein and each hydrogen.

10. 11. A compound of claim 10, which is 2-(diaminomethyleneamino)-4-(2-ureidomethylthiazol-4yl)thiazole.

11. 12. A compound of claim 8, wherein R 1 is hydroxy, halogen, cyano, carbamoyl, aminocarbamoyl, guanidinocarbamoyl, lower alkoxycarbonyl, lower alkanoyl, 25 benzimidazolylthio, triazolyl substituted with amino or a group of the formula : in which R 4 is hydrogen, cyano, carbamoyl, sulfamoyl, lower alkylsulfonyl and mono or di (lower)alkylsulfamoyl, and R 3 is amino or lower alkoxy, 16 1

12. 13. R is hydrogen, lower alkylcarbamoyl or 3 R is hydrogen, or 2 3 R and R are linked together to form lower alkylene, and A is bond. A compound of claim 12, wherein R 1 is lower alkoxycarbonyl, 2 3 R and R are each hydrogen.

13. 14. A compound of claim 13, which is 4-(2-(diaminomethyleneamino)thiazol-4-yl]thiazole-2carboxylic acid ethyl ester or its hydrobromide.

14. 15 15. A process for preparing a compound of the formula R 2 NH N X c=n4 J rW -Y-A-R wherein R 1 is amino which may have suitable substituent(s), hydroxy, halogen, cyano, acyl, heterocyclic thio, heterocyclic group or a group of the formula : in which R is hydrogen, cyano or acyl, and R 5 is amino or lower alkoxy, 2 3 R and R are each hydrogen, acyl or lower alkyl which may have halogen; or 2 3 R and R are linked together to form lower alkylene, 1G2 Y is 4or in which r6 is hydrogen or halogen, and A is bond or lower alkylene, provided that when R 1 is amino which may have suitable substituent(s) and A is bond; or R 1 is lower alkylthio ureido and A is lower alkylene, then Y is or a salt thereof, which comprises ‘N (1) reacting a compound of the formula : x 1 ch 2 co-y-a-r 1 wherein R 1 , A and Y are each as defined above, and X 1 is acid residue, or a salt thereof, with a compound of the formula : 25 R 2 NH S \ II C=N-C-NH~ 3 X 2 R NH 2 3 wherein R and R are each as defined above, 30 or a salt thereof, to give a compound of the formula : R 2 NH N-j—Y-A-R 1 XiUiJ rW 12 3 wherein R , R , R , A and Y are each as defined above, or a salt thereof, or (2) subjecting a compound of the formula : R 2 NH N-j—Y-A-R 1 YJ, r 3 nh 2 3 wherein R , R , A and Y are each as defined above, and R 1 is protected amino, or a salt thereof, to elimination reaction of the amino protective group, to give a compound of the formula : R 2 NH r 3 nh N Y-A-NH 2 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, or 25 (3) subjecting a compound of the formula : R 2 NH N-—Y-A-NHkW 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, to acylation, to give a compound of the formula : .5 3

15. 16 4 R 2 NH C=N RNH Y-A-R? D 2 3 wherein R , R , A and Y are each as defined above, and R 1 is acylamino, or a salt thereof. or 4) reacting a compound of the formula -Y-A-NH, C=NR 3 NH 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, with a compound of the formula (r’) 2 c =z-R 8 wherein R is lower alkylthio or protected hydroxy, a o R is hydrogen, cyano, nitro or acyl, and Z is N or CH, to give a compound of the formula : R 2 NH N- r 2 3 7 8 wherein R , R , R , R , A, Y and Z are each as a defined above, or a salt thereof, or Z-R Y-A-NHCR 105 5) reacting a compound of the formula Z-R R 2 NH r 3 nh N-r—Y-A-NHCR wherein R 2 , R 3 , r\ R 3 , A, Y and Z are each as a defined above, or a salt thereof, with a compound of the formula : hr£ wherein R^ is amino which may have suitable substituent (s), or a salt thereof, to give a compound of the formula: R 2 NH r 3 nh Z-R 11 7 -y-a-nhcr' 2 3 7 8 wherein R , R , R fc , R , A, Y and Z are each as defined above, or a salt thereof, or (6) reacting a compound of the formula R 2 NH N- r :=H— -Y-A-NH. r 3 nh' 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, with a compound of the formula 166 9 1 wherein R is suitable substituent in R as defined above, and X is acid residue or protected hydroxy, to give a compound of the formula : R 2 NH N--t-Y-A-NHR 9 X c=»jJ r 3 nh 2 3 9 wherein R , R , R , A and Y are each as defined above, or a salt thereof, or (7) reacting a compound of the formula : R 2 NH C=Nr 3 nh N-CN 11 7 -y-a-nhc-r' 2 3 7 wherein R , R , R , A and Y are each as defined cl above, or a salt thereof, with a compound of the formula : r 10 nhnh 2 wherein R 19 is hydrogen or lower alkyl, to give a compound of the formula : NH. NR 2 NH II N-—Y-A-NH—U n xN C=N r 3 nh x JO 2 3 10 wherein R , R , R , A and Y are each as defined above, or a salt thereof, or 5 (8) subjecting a compound of the formula : NH 2 11 1 R NH N-n-COCH-SC-A-R \ |IJ 2 C=N—k > 3> 7 s RNH 12 3 wherein R , R , R and A are each as defined above, or a salt thereof, to ring closure, to give a compound of the formula : R 2 NH r 3 nh 12 3 wherein R , R , R and A are each as defined above, or a salt thereof, or (9) reacting a compound of the formula R 2 NH N-t-COCH 2 X' in-r r 3 nh 2 3 wherein R and R are each as defined above, and X is acid residue, or a salt thereof, with a compound of the formula S II H 2 N-C-A-R 1GH wherein R and A are each as defined above, or a salt thereof, to give a compound of the formula: R 2 NH R 3 NH N-,-:-N x i< ί h i i C=N—< „7—A-R wherein R , R^, R and A are each as defined above, or a salt thereof, or (10) subjecting a compound of the formula : r 2 nh r 3 nh \ H '1 c=n-L s J NCN II -Y-A-C-NH. 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, to hydrolysis reaction, to give a compound of the formula : N-CONH. R 2 NH R 3 NH^ Nc=n—h -Y-A-C-NH. 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, or (11) reacting a compound of the formula R 2 NH -Y-A-NH, r 3 nh 109 2 3 wherein R% R , A and Y are each as defined above, or a salt thereof, with a compound of the formula : N-R R -CH wherein R 11 is protected hydroxy, and R 12 is acyl, to give a compound of the formula : 2 3 12 wherein R , R , R , A and Y are each as defined above, or a salt thereof, or (12) reacting a compound of the formula : X C=N—U. J) 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, with a compound of the formula : R 13 -OH wherein R is lower alkyl, to give a compound of the formula : 16. 17 0 NH R 2 NH N-Y-A-C-OR r 3 nh 2 3 13 wherein R , R , R , A and Y are each above, or a salt thereof, or as defined 13) reacting a compound of the formula : NH R 2 NH R 3 NH' -Y-A-C-OR 2 3 13 wherein R , R , R , A and Y are each above, or a salt thereof, with a compound of as defined the formula nh 2 r wherein R is acyl or cyano, to give a compound of the formula R 2 NH r 3 nh :=n-1L N-R II N-—Y-A-C-NH 2 3 14 wherein R , R , R , A and Y are each above, or a salt thereof, or as defined 17 1 r 15 s (14) reacting a compound of the formula : N-p-Y-A-F 1 C=N-IiJ h 2 n wherein R , A and Y are each as defined above, and 15 R is lower alkyl, or a salt thereof, with a compound of the formula : h 2 n-q-nh 2 wherein Q is lower alkylene, or a salt thereof, to give a compound of the formula z\ Q C=N-4 J -Y-A-R wherein R , A, Q and Y are each as defined above, or a salt thereof, or 25 (15) reacting a compound of the formula : r 15 s C=NI) -Y-A-R r 3 nh 1 3 15 wherein R , R , R , A and Y are each as defined above, or a salt thereof, with a compound of the formula nh 2 -r2 17.'i wherein R is lower alkyl which may have halogen, to CL give a compound of the formula : r 2 nh a R 3 NH Y-A-R 1 12 3 wherein R , R , R , A and Y are each as defined CL above, or a salt thereof, or (16) subjecting a compound of the formula : NH R 2 NH N-Y-A-C-OR r 3 nh 2 3 13 wherein R , R , R , A and Y are each as defined above, or a salt thereof, to hydrolysis reaction, to give a compound of the formula : R 2 NH Ν-—Y-A-CO-R 13 XnXJ AZ 2 3 13 wherein R , R , R , A and Y are each as defined above, or a salt thereof, or (17) subjecting a compound of the formula : 17 3 R 2 NH r 3 nh N —Y-A-CO-R 13 C=nX s J 2 3 13 wherein R , R , R , A and Y are each as defined above, or a salt thereof, to amidation reaction, to give a compound of the formula : R 2 NH r 3 nh C=N- -y-a-conh 2 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, or (18) reacting a compound of the formula : X C=N-X J r 3 nh^ 2 3 13 wherein R , R , R , A and Y are each as defined above, or a salt thereof, with hydrazine, to give a compound of the formula : R 2 NH Y-A-CONHNH 2 r 3 nh 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, or (19) reacting a compound of the formula : 174 r 2 nk N— C=U -Y-A-CONHNH. r 3 nh 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, with S-(lower alkyl)isothiourea or a salt thereof, to give a compound of the formula R 2 NH NNH II -Y-A-CONHNH-C-NH, C=Nr 3 nh 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, or (20) subjecting a compound of the formula : r 2 nh C=NNNH II -Y-A-CONHNH-C-NH, r 3 nh 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, to ring closure, to give a compound of the formula : R 3 NH' R 2 NH 2 3 wherein R , R , A and Y are each as defined above, 175 or a salt thereof, or (21) subjecting a compound of the formula : R 2 NH N--t—Y-A-R 1 \ II I c c=n—-LL 3 / b RNH 2 3 wherein R , R , A and Y are each as defined above, and R 1 is acylamino having protected hydroxy, or a salt thereof, to elimination reaction of the hydroxy protective group, to give a compound of the formula : 3 X R J NH R 2 NH 2 3 wherein R , R , A and Y are each as defined above, and R 1 is acylamino having hydroxy, or a salt thereof, or 25 (22) subjecting a compound of the formula : H_N N-j—Y-A-R 1 2 h 2 n wherein R 1 , A and Y are each as defined above, or a salt thereof, to acylation reaction, to give a compound of the formula : 176 r 2 nh N-Y-A-R := N —Li H 2 N wherein R , A and Y are each as defined above, and R^ is acyl, or a salt thereof, or 23) subjecting a compound of the formula R 2 NH -Y-A-CONH. r 3 nh 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, to dehydration reaction, to give a compound of the formula : R 2 NH N-Y-A-CN 3 X s R NH 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, or 24) subjecting a compound of the formula R 2 NH N-y-co 2 r C=N30 3 X R NH 2 3 wherein R , R and Y are each as defined above, and R 16 is lower alkyl, or a salt thereof, to reduction reaction, to give a compound of the formula : 177 r 2 nh r 3 nh -Y-CH 2 OH wherein R , R J and Y are each as defined above, or a salt thereof, or (25) subjecting a compound of the formula R 2 NH N-r—Y-A-OH C=N15 r 3 nh 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, to halogenation reaction, to give a compound of the formula : R 2 NH r 3 nh -Y-A-R 2 3 wherein R , R , A and Y are each as defined above, and R 1 is halogen, or a slat thereof, or (26) reacting a compound of the formula : R 2 NH N-—Y-A-R 1 3 F' R NH 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, with a compound of the formula 17 8 Η - R 1 wherein R^ is heterocyclic thio, to give a compound of the formula : R 2 NH N-—Y-A-R 1 3 b R NH 12 3 wherein R^, R , R , A and Y are each as defined above, or a salt thereof, or (27) subjecting a compound of the formula : R 2 NH N-Y-CH 2 OH C=Nr 3 nh 2 3 wherein R , R and Y are each as defined above, or a salt thereof, to oxidation reaction, to give a compound of the formula : R 2 NH R 3 NH N-—Y-CHO 2 3 wherein R , R and Y are each as defined above, or a salt thereof, or (28) subjecting a compound of the formula : R 2 NH r 3 nh -Y-A-CN 179 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, to hydrolysis reaction, to give a compound of the formula : R 2 NH r 3 nh C=N -y-a-conh 2 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, or ί 29) reacting a compound of the formula : R 2 NH -Y-A-R C=Nr 3 nh 12 3 wherein R e , R , R , A and Y are each as defined above, or a salt thereof, with a compound of the formula M wherein R 1 g M to give a is imino, and is alkali metal, compound of the formula : R 2 NH r 3 nh C=N -Y-A-R 3 12 3 wherein R , R , R , A and Y are each as defined g above, or a salt thereof, or 17. 18 0 (30) reacting a compound of the formula r 2 NH N-r—Y-A-Rt II I g C=N—4 > r 3 nh 12 3 wherein R , R , R , A and Y are each as defined g' ' ’ above, or a salt thereof, with hydrazine hydrate, to give a compound of the formula : R 2 NH N-—Y-A-NH, C=NR 3 NH 2 3 wherein R , R , A and Y are each as defined above, or a salt thereof, or (31) subjecting a compound of the formula : R 3 NH R 2 NH 12 3 wherein R , R , R and A are each as defined above, and r6 is halogen, or a salt thereof, to hydrogenation reaction, to give a compound of the formula : 18 1 12 3 wherein R , R , R and A are each as defined above, or a salt thereof, or (32) subjecting a compound of the formula : R 2 NH -y-a-rJ; R 3 NH' 2 3 wherein R , R , A and Y are each as defined above, and R^ is acylamino having protected amino, or a salt thereof, to elimination reaction Of the amino protective group, to give a compound of the formula : R 2 NH R 3 NH Y-A-R 1 2 3 wherein R , R , A and Y are each as defined above, and R 1 is acylamino having amino, or a salt thereof.

16. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.

17. A method for the treatment of ulcer which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals. 18.

18. 19.

19. 20.

20. 21. 15 22. 23. 24 . 18. 19. 20.

21. 15 22. 23. 24 . A use of a compound of claim 1 as a medicament. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as antiulcer agent or H 2 -receptor antagonist. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified. A process for preparing a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified. A compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in a preceding claim. A pharmaceutical composition according to claim 16, substantially as hereinbefore described. Use according to claim 18 or 19, substantiallyas hereinbefore described.